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Jo^f  CORNELL  UNIVERSITY*, 

*B?i±-    *   — 7 

/St  3  THE  -    -- 

BostwcU  p.  gFforoei*  SSfoarg.-' 

""  THE  GIFT  OF 

-"'  '..ROSWELE "P.  FLOWER-    4     "\ 

FOR  THE  IJSEOF 
!    tfHE   N.   V.    STATE   VETERINARY   COLLEGE. 

*    "  X897 


CORNELL  UNIVERSITY  LIBRARY 


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PHARMACOLOGY,  THERAPEUTICS 

AND 

MATERIA"  MEDICA 


*■ 


A   TEXT-BOOK 


OF 


PHARMACOLOGY,  THERAPEUTICS 


AND 


MATERIA  MEDICA 


BY 

T.  LAUDEE  ptUNTON,  M.D.,  D.Sc,  F.E.S. 

FELLOW  OF  THE  ROYAL  COLLEGE  OF  PHYSICIANS;  ASSISTANT  -  PHYSICIAN  AND  LECTDREB- 

ON   MATERIA   MEDICA   AT  ST   BARTHOLOMEW'S   HOSPITAL;    EXAMINER   IN   MATERIA 

MEDICA  IN  THE  UNIVERSITIES  OF  OXFORD  AND  OF  LONDON  ;  LATE  EXAMINER 

IN  THE  UNIVERSITY  OF  EDINBURGH,  IN  THE   VICTORIA  UNIVERSITY, 

AND  IN   THE  ROYAL  COLLEGE  OF  PHYSICIANS,  LONDON 


ADAPTED    TO    THE 

Wmittlt  states;  $&armaw>;poeta 

FRANCIS    H.   WILLIAMS,    M.D.Boston,   Mass. 
THIRD   EDITION 

CONTAINING   THE 

ADDITIONS  (1891)  TO  THE  BBITISH  PHABMACOPCEIA 

Hon&on 
MACMILLAN    AND    CO. 

AND    NEW    YORK 

1893 
« 

The  right  of  translation  is  reserved 


First  edition  printed  1885 ;  second,  March'  1887 ;  Addenda  inserted  July  1887 
Additions  (1891)  to  the  British  Pharmacopoeia.    Reprinted  November  1891,1893. 


TO 

fflje  'gKemorB  of 
SIR  EOBEET  CHRISTISON,  Baet.  &c. 

HIS   HONOURED   TEACHEB 

AND   TO 

CARL    LUDWIG 

HIS   BELOVED   MASTER 

THIS   BOOK    IS    GBATEFULLY    DEDICATED 

BY 

THE  AUTHOE 


PBEFACE 

TO 

THE    THIED    EDITION. 


The  rapid  exhaustion  of  the  second  edition  of  this  work  has  pre- 
vented me  from  making  as  many  improvements  in  the  present 
edition  as  I  could  have  desired.  At  the  same  time  I  have  tried,, 
as  far  as  the  short  time  at  my  disposal  would  allow,  to  amend 
the  imperfections  of  former  editions,  as  well  as  to  bring  the  work 
up  to  date  and  render  it  more  useful  by  the  introduction  of  new 
matter. 

The  treatment  of  one  of  the  most  important  portions  of  Phar- 
macology, viz.  the  Connection  between  Chemical  Constitution 
and  Physiological  Action,  is  still  very  meagre,  because  I. find  that 
the  size  of  this  work  would  be  too  much  increased  were  I  to  treat 
the  subject  fully,  and  I  am  therefore  preparing  a  small  text-book 
upon  it. 

The  struggle  for  existence  between  microbes  and  the  living 
organism,  which  in  the  first  edition  was  only  illustrated  by  a 
single  diagram  of  a  bacillus  and  amoeba,  is  now  fully  illustrated 
by  woodcuts  copied  from  Metschnikoff's  paper.  The  views  of 
Hughlings  Jackson  on  the  nervous  system  have  been  illustrated 
by  a  diagram  which,  when  covered  with  successive  layers  of  thin 
and  semi-transparent  paper,  exhibits  the  effect  of  anaesthetics 
and  narcotics  in  successively  abolishing  various  faculties.  The 
recent  work  of  Kiihne  and  Politzer  on  the  mode  of  action  of 
curare  has  been  noticed,  and  the  pathology  of  tremor  discussed. 
The  section  on  the  action  of  drugs  upon  the  eye  has  been  care- 
fully revised.  The  section  on  antipyretics  has  been  rendered 
somewhat  fuller,  and  some  diagrams  illustrating  the  pathology, 
of  fever  and  the  mode  of  action  of  antipyretics  have  been  intro* 
duced,*  but  it  is  very  difficult  in  the  present  state  of  our  know- 
ledge to  deal  satisfactorily  with  this  subject.    Paragraphs  on.thei 


viii  PEEFACE   TO  THE 

treatment  of  cough  and  on  the  pathology  and  treatment  of 
asthma  have  been  introduced.  The  researches  of  Adami  on 
diuretics  have  been  noticed,  but  they  have  not  necessitated  any 
essential  change  in  the  text,  as  the  communication  between  the 
portal  vein  of  the  kidney  and  the  renal  artery  had  been  already 
allowed  for  in  describing  Nussbaum's  researches  in  the  first 
edition.  The  views  expressed  in  the  first  edition  regarding  the 
mode  of  action  of  caffeine  have  been  confirmed  and  extended  by 
the  observations  of  Schroeder  and  Munk.  The  researches  of 
Jendrassik  on  the  diuretic  action  of  calomel  and  the  explanation 
advanced  by  Locke  have  been  noticed. 

The  arrangement  of  the  Vegetable  Materia  Medica  has  been 
almost  entirely  remodelled  on  Hooker's  plan,  and  a  short  intro- 
duction has  been  added  to  it,  in  which  I  have  tried  to  show  the 
use  of  botanical  arrangement,  as  well  as  to-  protest  against  the 
abuse  of  it  in  the  examination  of  students  in  Materia  Medica. 

By  the  use  of  small  type  for  matters  which  are  of  practically 
little  interest  to  general  students,  and  yet  are  occasionally  wanted 
for  reference,  a  certain  amount  of  space  has  been  gained,  at  the 
same  time  that  the  general  student  is  enabled  at  a  glance  to 
distinguish  the  parts  which  are  of  little  or  no  interest  to  him. 
Notwithstanding  my  efforts  to  condense  it,  the  present  edition 
contains  about  120  pages  more  than  the  second,  but  by  using 
thinner  paper  the  bulk  of  the  volume  has  been  little,  if  at  all, 
increased. 

The  General  Index  has  been  carefully  revised.  The  Index  of 
Diseases  and  Eemedies  ha3  been  revised  to  a  certain  extent,  but 
it  still  remains  a  mere  skeleton  of  what  it  ought  to  be.  It  is 
little  more  than  a  list  of  drugs  which  have  been  recommended 
by  somebody  or  other  at  some  time  or  other  in  the  treatment  of 
certain  diseases.  In  a  few  instances  the  conditions  supposed  to 
indicate  the  use  of  one  drug  in  preference  to  another  have  been 
given,  but  I  have  not  yet  been  able  to  sift  the  statements  which 
have  been  made  regarding  the  different  drugs.  The  only  use  of 
the  Index  at  present  is  simply  to  remind  the  practitioner  who  is 
treating  a  disease  of  the  names  of  drugs  which  have  been  proposed 
as  remedies  for  it.  Thus,  under  the  head  of  Hydrophobia  I  have 
mentioned  a  number  of  remedies  which  have  been  used  or  pro- 
posed, because  those  who  may  have  to  treat  a  case  of  this  disease 
may  wish  to  try  some  remedy,  although  my  own  experience  leads 
me  to  think  that  almost  all  well-marked  cases  will  have  a  fatal 
isBue  whatever  the  drugs  employed  may  be. 


THIED  EDITION.  ix 

The  idea  of  a  Therapeutic  Index  was  taken  from  that  in 
Ringer's  '  Therapeutics,'  and  I  wished  to  make  one  still  more  full 
and  complete  by  comparing  his  index  with  those  of  Bartholow  and 
H.  C.  Wood,  with  Waring's  '  Therapeutics,'  and  with  the  wonder- 
ful '  Medical  Digest '  of  Dr.  Neale.  After  I  had  begun  to  do  this, 
I  found  that  a  similar  idea  had  occurred  to  Dr.  S.  0.  L.  Potter, 
who  had  already  published  an  index  of  '  Comparative  Thera- 
peutics,' in  which  he  gave  a  list  of  remedies  taken  from  the  works 
of  Aitken,  Bartholow,  Niemeyer,  Phillips,  Piffard,  Binger,  Stille, 
Tanner,  Trousseau,  H.  C.  Wood,  Waring,  and  some  others. 
After  finding  that  Dr.  Potter  had  already  compared  together 
more  works  than  I  expected  to  do,  I  used  his  list,  along  with 
Naphey's  '  Medical  Therapeutics '  and  Neale's  '  Medical  Digest,' 
in  preparing  my  Index.  I  was  unable,  however,  even  with  the 
aid  of  these  works,  to  make  the  Index  anything  more  than  a 
mere  list  of  names,  excepting  in  a  few  instances.  So  imperfect 
was  it,  indeed,  that  up  to  the  last  moment  I  intended  to  cancel 
it,  and  would  have  done  so  had  not  a  case  occurred  in  my  own 
practice  which  showed  me  that  even  a  mere  list  of  drugs  may 
sometimes  be  desirable.  I  was  not  unmindful  of  the  old  adage 
that  '  Fools  and  children  should  not  see  half-done  things,'  but  I 
felt  confident  that  the  majority  of  my  readers  would  not  belong 
to  either  of  these  classes,  and  so  I  allowed  the  Index  to  remain. 
My  intention  to  cancel  it,  however,  led  me  to  omit  an  acknow- 
ledgment of  my  indebtedness  to  Dr.  Potter,  and  I  have  pleasure 
in  acknowledging  it  now. 

My  use  of  Dr.  Potter's  book  has  led  me  to  include  in  the 
Therapeutic  Index  one  remedy  which  the  homoeopaths  claim  as 
theirs.  His  book  contains  a  list  of  remedies  taken  from  homoeo- 
pathic works  as  well  as  from  those  I  have  already  named.  The 
two  classes  of  remedies  are  kept  apart  in  different  columns ;  but 
I  find  that,  in  one  instance  at  least,  the  amanuensis  whom  I 
employed  to  copy  out  a  number  of  the  drugs  from  Dr.  Potter's 
book  has  made  a  mistake  in  the,  column,  and  has  taken  '  Apis '  as 
a  remedy  for  tonsillitis  from  the  Homoeopathic  column.  To  the 
best  of  my  knowledge  this  is  the  only  remedy  I  have  taken  from 
a  homoeopathic  source.  If  any  other  remedies  claimed  as 
-'  homoeopathic  '  have  been  introduced,  they  have,  I  think,  been 
copied  from  the  works  of  one  or  other  of  the  authors  already 
mentioned,  and  in  Dr.  Phillips's  work  there  are  some  remedies 
mentioned  without  references.  But  as  I  intended  up  to  the  last 
moment  to  cancel  the  whole  list,  my  revision  of  it  was  hasty  and 


x  PBEFACE   TO  THE 

imperfect;  and  as  I  omitted  to  expurgate  'Apis,'  I  may  also 
possibly  have  overlooked  other  remedies.  If  any  such  omission 
has  occurred  I  am  sincerely  sorry,  and  I  can  assure  the  homoeo- 
paths that  it  is  perfectly  unintentional. 

Perhaps  it  may  be  well  to  take  this  opportunity  of  saying  a 
few  words  in  regard  to  homoeopathic  remedies  and  homoeopathy 
generally. 

The  mere  fact  that  a  drug  in  small  doses  will  cure  a  disease 
exhibiting  symptoms  similar  to  those  produced  by  a  large  dose 
of  the  drug  does  not  constitute  it  a  homoeopathic  medicine,  for 
this  rule  was  known  to  Hippocrates,  and  the  rule  similia  simi- 
libus  curantur  was  recognised  by  him  as  true  in  some  instances. 
But  Hippocrates  was  not  a  homoeopath,  and  he  recognised  the 
fact  that,  while  this  rule  was  sometimes  true,  it  was  not  invari- 
ably so. 

It  seems  to  me  that,  in  founding  the  system  of  homoeopathy, 
Hahnemann  has  proceeded  with  his  facts  as  he  did  with  his  medi- 
cines— diluting  his  active  drugs  with  inert  matter,  and  diluting 
his  facts  with  much  nonsense. 

In  what  I  am  about  to  say,  I  may  be  to  some  extent  open  to 
correction,  for  I  cannot  claim  to  know  his  doctrines  so  thoroughly 
as  those  who  believe  in  and  follow  him.  So  far,  however,  as  I 
know  his  doctrines,  it  seems  to  me  that  they  consist  in  raising 
the  rule  similia  similibus  curantur  to  the  rank  of  a  regular  law ; 
in  claiming  a  curative  power  for  infinitesimal  doses,  and  in  be- 
lieving that  the  diminution  in  the  dose  of  the  drug  was  made  up 
for  by  the  potency  conferred  upon  it  through  prolonged  tritura- 
tion. It  is  no  doubt  true  that  in  some  instances  the  power  of  a 
drug  may  be  increased  by  trituration,  inasmuch  as  fine  subdivi- 
sion either  makes  it  more  easily  absorbed  or  alters  its  chemical 
composition,  as  in  the  case  of  mercurial  compounds,  where  the 
prolonged  exposure  to  the  air  and  friction  involved  in  the  tri- 
turation may  greatly  increase  the  power  of  the  drug  by  oxidising 
it,  and  changing  it  from  a  mercurous  to  a  mercuric  salt.  But 
in  both  cases  the  increased  activity  conferred  upon  the  drug  is 
strictly  limited,  although  it  may  be  great  in  the  case  of  the  salts 
of  mercury.  To  suppose  it  to  be  exerted  ad  infinitum  is  sheer 
nonsense,  and  the  absurdity  of  infinitesimal  doses  has  been  so 
often  demonstrated  that  it  is  useless  to  say  more  about  it. 

I  think  one  is  justified  in  describing  Hahnemann's  experiment 
with  cinchona  bark  as  the  foundation-stone  of  his  doctrine  of 
homoeopathy;  for  Dr.  NankivelL  in  his  Presidential  Address  to 


THIED  EDITION.  xi 

the  British  Homoeopathic  Congress  at  Norwich,  says,  with  regard 
to  the  action  of  quinine  in  ague,  that  '  it  was  this  very  instance 
of  successful  empirical  treatment,  of  specific  medicinaj  action, 
that  led  Hahnemann  first  to  investigate  the  actions  of  drugs  on 
the  healthy  human  frame,  and  thus  to  lay  "the  foundation  of  the 
most  complete  and  lucid  system  of  scientific  therapeutics  that 
the  world  has  yet  seen.'  But  I  have  shown  in  the  body  of  this 
work  (p.  52)  that,  although  Hahnemann's  observations  were  in 
all  probability  perfectly  correct,  the  conclusions  he  drew  from 
them  were  utterly  erroneous. 

But  there  is  another  side  to  the  question  which  I  think  it  is 
only  fair  to  consider  also.  While  Hahnemann's  theory  was 
certainly  bad,  there  can,  I  think,  be  little  doubt  that  he,  like 
Paracelsus  and  Priessnitz,  has  done  good  service  to  medical 
practice.  Paracelsus  gathered  information  from  shepherds,  wise 
women,  and  quacks  of  all  sorts,  and  thereby  obtained  a  know- 
ledge of  popular  remedies,  not  generally  employed  by  the  profes- 
sion, but  which  were  nevertheless  useful. 

Priessnitz  did  not  invent  the  use  of  cold  water  as  a  remedy, 
for  it  was  known  nearly  eighteen  hundred  years  before  his  time. 
Musa '  saved  the  life  of  Augustus  by  the  cold  bath,  but,  not 
knowing  exactly  how  and  when  to  employ  it,  he  killed  the  nephew 
of  the  Emperor  by  it,  and  such  failures  brought  the  treatment 
by  water  into  discredit.  Priessnitz  revived  it,  and  now  in  the 
use  of  cold  sponging,  wet  packs,  baths  and  douches  we  have  a 
powerful  means  of  treating  fever  and  curing  disease. 

Hahnemann  also  did  good,  and  the  system  which  he  founded 
has  done  great  service  by  teaching  us  the  curative  power  of 
unaided  Nature,  the  use  of  diet  and  regimen  in  treating  disease, 
and  the  more  than  inutility,  the  actual  hurtfulness,  of  powerful 
drugs  in  many  instances.  The  physician  is  bound  to  do  the 
very  utmost  he  can  for  his  patient,  and  his  very  anxiety  has 
frequently  led  him  to  do  harm.  He  has  been  afraid  to  leave  the 
cure  of  disease  to  Nature,  and  by  the  administration  of  powerful 
drugs  has  frequently  injured  instead  of  benefited  his  patient. 
The  use  of  infinitesimal  doses  which  could  not  affect  the  body 
of  the  patient  one  way  or  the  other,  but  kept  the  mind  of  both 
patient  and  physician  easy,  and  allowed  the  vis  medicatrix  natures 
free  scope,  has  helped  us  to.  a  more  perfect  knowledge  of  the 
natural  course  of  disease.  The  use  of  infinitesimal  doses  has  also 
led  to  much  care  being  bestowed  by  those  who  use  them  upon 
diet  and  regimen.     When  a  physician  administered  a  large  dose 


xii  PEEFACB   TO  THE 

of  tartar  emetic  or  of  salts  and  senna,  he  knew  that  his  remedies 
would  produce  vomiting  or  purgation  respectively  with  consider- 
able certainty,  whatever  the  diet  or  regimen  of  the  patient  might 
be ;  but  the  case  was  quite  different  with  infinitesimal  doses.  If 
a  patient  was  being  treated  with  carbo  vegetabilis  in  the  thirtieth 
dilution,  the  utmost  care  was  necessary  in  regard  to  his  diet,  for 
if  he  happened  to  eat  a  single  piece  of  burned  toast  at  breakfast, 
he  would  consume  at  the  one  meal  as  much  vegetable  charcoal 
as  would,  when  properly  diluted,  have  served  him  for  medicine 
during  the  remainder  of  his  natural  life. 

Moreover,  the  homoeopathic  practice  of  giving  only  one  drug 
has  tended  greatly  to  dimmish  the  practice  of  polypharmacy,  and 
the  tinctures,  powders,  and  globules  they  employ  show  us  a  good 
example  in  regard  to  the  administration  of  remedies  in  ah  agree- 
able form.  But,  although  this  mode  of  practice  may  be  employed 
by  homoeopaths,  it  is  not  homoeopathic.  We  are  not  homoeopaths 
because  we  use  a  single  drug  at  a  time  and  give  half  an  ounce  of 
infusion  of  digitalis  to  a  patient  suffering  from  heart-disease 
without  thinking  it  necessary  to  mix  it  with  broom,  squill,  or 
spirit  of  nitrous  ether.  Nor  are  we  homoeopaths  because  we  use 
l-50th  of  a  grain  of  digitalin  instead  of  the  infusion  of  digitalis. 
Nor  are  we  homoeopaths  even  if  we  get  a  manufacturing  chemist 
.to  make  up  the  digitalin  into  a  globule  with  a  quarter  of  a  grain 
of  sugar  of  milk  instead  of  with  five  grains  of  extract  of  Kquorice. 
Nor  do  we  become  homoeopaths  merely  because  we  may  employ 
a  small  dose  instead  of  a  large  one,  and  begin  with  ten  drops  of 
the  infusion  of  digitalis  instead  of  half  an  ounce. 

It  is  not  the  use  of  a  single  drug  at  a  time,  of  a  small  dose, 
of  a  globule,  nor  even,  as  we  have  already  seen,  of  a  drug  which 
may  produce  symptoms  similar  to  those  of  the  disease,  that  con- 
stitutes homoeopathy.  The  essence  of  homoeopathy,  as  es- 
tablished by  Hahnemann,  lies  in  the  infinitesimal  dose  and  the 
universal  application  of  the  rule  similia  similibus  curaniur.  But 
the  infinitesimal  doses  are  so  absurd  that  I  believe  they  have 
been  discarded  by  many  homoeopaths.  To  such  men  all  that 
remains  of  homoeopathy  is  the  universality  of  the  rule  similia 
similibus  curantur,  and  the  only  difference  between  them  and 
rational  practitioners  lies  in  the  fact  that  the  latter  regard  the 
rule  as  only  of  partial  application.  At  first  sight  this  difference 
may  seem  to  be  only  slight,  but  it  is  not  so  in  reality ;  for  white 
the  rational  practitioner,  refusing  to  be  bound  by  any  '  pathy,' 
whether  it  be  allopathy,  antipathy,  or  homoeopathy,  seeks  to 


THIED  EDITION.  xiii 

trace  each  symptom  back  to  the  pathological  change  which  caused 
it,  and,  by  a  knowledge  of  the  action  of  drugs  on  each  tissue  and 
organ  of  the  body,  to  counteract  these  pathological  changes,  the 
homoeopath  professes  to  be  in  possession  of  a  rule  which  will 
enable  him  to  select  the  proper  remedy  in  each  case  by  a  consi- 
deration of  the  symptoms,  without  reference  to  the  pathological 
condition.  He  may  thus  dispense  with  anatomy,  physiology, 
pathology,  and  pharmacology.  All  that  is  necessary  is  a  list  of 
morbid  symptoms  on  the  one  hand,  and  a  list  of  the  symptoms 
produced  in  healthy  men  by  various  drugs  on  the  other. 

It  is  the  falsity  of  the  claim  which  homoeopathy  makes  to 
be  in  possession,  if  not  of  the  universal  panacea,  at  least  of  the 
only  true  rule  of  practice,  that  makes  homoeopathy  a  system  of 
quackery ;  yet  this  arrogant  claim  constitutes  the  essence  of  the 
system,  and  the  man  who,  leaving  Hahnemann  and  going  back 
to  Hippocrates,  regards  the  rule  similia  similibus  curantur  as 
only  of  partial  and  not  of  universal  application,  has  no  longer 
any  right  to  call  himself  a  homoeopath. 

Yet  we  hear  some  leading  homoeopaths  say,  'We  do  not 
claim  any  exclusiveness  for  our  method,' '  and  then  complain 'that 
they  are  excommunicated  by  the  medical  profession.  If  they 
have  renounced  the  errors  of  Hahnemann's  system,  they  ought 
not  to  retain  its  name,  but  frankly  acknowledge  their  error  and 
return  to  rational  medicine,  of  which  Hippocrates  is  regarded 
as  the  father.  As  a  medical  man  is  bound  to  do  his  utmost  for 
the  good  of  his  patient,  it  is  obvious  that,  although  he  may 
employ  baths  or  packs  as  a  mode  of  treatment,  he  cannot, 
without  becoming  untrue  to  his  profession,  throw  aside  all  other 
means  of  treatment  and  become  a  hydropath ;  nor  can  he  consult 
on  equal  terms  with  those  who,  either  through  ignorance  or 
wilful  blindness,  deny  the  use  of  other  means  of  cure  and  limit 
themselves  to  the  application  of  water.  What  is  true  of  hydro- 
pathy is  true  of  homoeopathy.  I  dislike  controversy  extremely, 
and  should  not  have  taken  up  so  much  of  the  preface  with  con- 
troversial matter  had  I  not  been  forced  to  defend  myself  by  the 
attacks  which  certain  homoeopaths  have  made  upon'  me. 

I  may  now  turn  to  the  pleasanter  task  of  acknowledging  my 
indebtedness  to  many  friends  who  have  helped  me  in  the  pre- 
paration of  this  edition.  In  addition  to  some  of  those  who 
helped  me  with  former  editions,  I  have  to  thank  Dr.  Hughlings 

1  Preface  by  Eichard  Hughes  to  The  Medical  Treatment  of  our  Time.  London : 
Unwin  Brothers,  Ludgate  Hill. 


xiv  PEEFACE   TO  THE   THIED  EDITION. 

Jackson  for  assistance  in  the  construction  of  the  diagram 
which  illustrates  his  views  of  the  nervous  system ;  Mr.  W.  H. 
Jessop  and  Mr.  Tweedy  for  much  aid  and  many  suggestions  in 
revising  the  section  on  diseases  of  the  eye ;  and  I  am  especially 
grateful  to  my  friend,  Dr.  Thin,  who  has  greatly  added  to  the 
value  of  the  book  by  writing  an  account  of  the  uses  of  various 
remedies  in  skin  diseases.  I  am  indebted  to  Mr.  Whitehead,  Dr. 
Halliburton,  and  especially  to  Dr.  Sidney  Martin,  for  their  assist- 
ance in  passing  this  edition  through  the  press.  To  Dr.  Martin 
I  am  also  indebted  for  many  valuable  suggestions,  and  for  such 
an  amount  of  help  that,  but  for  him,  the  preparation  of  this 
edition  would  certainly  have  been  delayed  for  many  months. 

T.  LAUDEE   BEUNTON. 
March,  1887. 


PBEFACE 


TO 


THE    FIEST    EDITION. 


Some  apology  is  required  for  the  long  delay  in  the  appearance 
of  this  work,  for  a  number  of  years  have  now  elapsed  since  it  was 
advertised  as  being  in  the  press.  More  than  fifteen  years  ago,  I 
had  a  work  on  Materia  Medica  completely  written  out  and  ready 
for  the  printer.  Some  time  afterwards,  all  the  arrangements 
had  been  made  for  its  publication,  and  in  the  course  of  a  few 
weeks  it  was  to  have  been  issued  from  the  press.  Just  as  I  was 
about  to  send  it  to  the  printer,  however,  I  asked  for  a  little 
delay  in  order  that  I  might  make  some  improvements  and  remove 
some  redundancies,  for  the  work  as  it  then  stood  was  considerably 
larger  than  the  present  one. 

As  I  went  through  it,  I  found  so  many  unsatisfactory  state- 
ments and  uncertainties  regarding  the  mode  of  action  of  drugs, 
which  I  thought  I  could  decide  by  a  few  experiments,  that  I 
wished  for  a  little  time  in  order  that  those  doubtful  points  might 
be  settled ;  but  as  I  went  on  the  labour  grew,  other  engage- 
ments became  pressing,  and  longer  and  longer  delay  was  required. 
From  greater  experience  as  a  teacher  and  examiner  also,  I  came 
to  the  conclusion  that  the  plan  of  the  work  might  be  altered 
with  advantage  ;  and  so  finally  the  whole  manuscript  was  thrown 
aside,  and  the  book  entirely  re-written. 

In  the  original  work  I  discussed  the  physiological  and  thera- 
peutical actions  of  each  drug  separately,  in  the  same  way  as  in 
the  third  part  of  the  present  work,  though  on  a  much  more 
extended  scale.  I  found,  however,  that  this  plan  necessitated  a 
good  deal  of  repetition  regarding  the  experimental  methods  by 
which  the  action  of  the  drugs  had  been  ascertained. 

Moreover,  the  physician  does  not  want  to  know  only  what  the 
actions  of  any  one  drug  are ;  he  rather  requires  a  knowledge  of 


xvi  PREFACE   TO  THE 

classes  of  drugs,  and  of  the  manner  in  which  the  actions  of  the 
individual  members  of  a  class  differ  from  each  other.  He  requires, 
in  fact,  a  knowledge  of  the  ways  in  which  the  various  functions 
of  the  body  can  be  influenced  by  drugs  both  in  health  and 
disease,  in  order  that  he  may  restore  health  to  his  patients. 

It  has  appeared  to  me,  therefore,  better  to  devote  a  complete 
section  of  the  work  to  a  discussion  of  the  methods  by  which 
the  action  of  drugs  is  determined;  io  the  manner  in  which 
each  function  of  the  body  can  be  modified  by  drugs  ;  and  to  the 
general  rationale  of  the  use  of  drugs  in  disease,  i.e.  to  devote  a 
section  to  general  pharmacology  and  general  therapeutics. 

Considerable  experience  both  in  teaching  and  examining 
has  shown  me  that  students  sometimes  find  a  difficulty  in 
applying  physiology  to  pharmacology  and  therapeutics,  and  I 
find  that  many  others  are,  like  myself,  apt  to  forget  those  parts 
of  physiology  which  they  are  not  constantly  studying.  I  have 
therefore  thought  it  well,  for  the  sake  both  of  students  and 
practitioners,  to  give  a  short  account  of  the  normal  functions  of 
the  different  parts  of  the  body,  before  proceeding  to  discuss  the 
alterations  which  are  produced  in  them  by  drugs,  or  which  they 
undergo  in  disease.  In  the  case  of  the  heart  and  the  kidneys 
also,  where  the  action  of  drugs  is  complicated  and  difficult,  I  have 
found  it  necessary  to  enter  a  little  more  fully  into  the  physiology 
of  these  organs  than  is  done  in  the  ordinary  text-books." 

I  have  found  that  a  similar  difficulty  occurs  with  pathology 
as  with  physiology,  and  I  have  therefore  occasionally  discussed 
pathological  questions  when  I  have  thought  that  by  doing  so  I 
could  render  the  action  of  drugs  in  disease  more  intelligible,  and 
thus  aid  the  student  of  rational  therapeutics. 

In  the  second  part  of  the  work  on  general  pharmacy,  I  have 
classed  together  the  various  pharmaceutical  preparations,  and 
given  lists  of  them  for  reference.  It  is  by  no  means  my  intention 
that  these  should  be  learned  by  heart  by  any  student,  and  indeed 
I  think  it  is  well  to  take  this  opportunity  of  protesting  against 
the  injustice  of  the  demands  which  are  sometimes  made  upon  the 
memories  of  students. 

It  is  probable  that  the  majority  of  the  best  and  most  successful 
practitioners  would  be  very  much  puzzled  if  they  were  required  to 
state  the  exact  quantity  of  every  ingredient  in  each  pill  or  each 
ointment  that  they  prescribe,  or  the  exact  quantity  of  the  crude 
drug  from  which  the  infusions  or  tinctures  which  they  use  have 
been  made.     They  know  the  action  .of  the  pill  or  ointment,  they 


FIEST  EDITION.  xvii 

know  the  action  of  the  infusion  or  tincture,  and  they  do  not  trouble 
themselves  about  details  which  are  only  useful  to  the  chemist  who 
is  making  up  the  preparation. 

It  is  very  greatly  to  be  regretted,  for  it  is  a  stumbling-block  in 
the  way  of  true  progress,  that  students  who  have  afterwards  to 
become  medical  practitioners  and  not  pharmaceutical  chemists, 
should  be  asked  at  examinations  the  quantities  of  crude  drugs 
from  which  particular  preparations  are  made — quantities  which 
even  the  manufacturing  chemist  himself  would  never  dream  of 
carrying  in  his  memory,  but  would  obtain  by  reference  to  his  books 
whenever  he  required  them.  As  the  late  Professor  Sharpey  used 
very  truly  to  say,  '  You  may  as  well  require  of  a  medical  student 
a  knowledge  of  the  whole  art  of  cutlery  before  you  set  him  to 
dissect.'  Medical  science  is  now  advancing  in  every  direction,  and 
unless  we  cut  off  some  of  the  less  useful  kinds  of  information, 
which  medical  students  were  formerly  obliged  to  acquire,  it 
becomes  impossible  for  them  to  learn  all  that  is  truly  valuable.  In 
Materia  Medica  we  now  oblige  them  to  learn  the  physiological 
action  of  drugs,  a  subject  regarding  which,  until  quite  recently, 
little  or  nothing*  was  known,  and  to  oblige  them  to  learn  all  this,  in 
addition  to  what  they  were  formerly  expected  to  know,  is  to  treat 
them  as  Pharaoh  treated  the  Israelites,  and  compel  them  to  make 
the  same  number  of  bricks,  while  giving  them  no  straw. 

I  am  so  much  impressed  with  the  necessity  of  lessening  the 
amount  of  unnecessary  work  sometimes  required  as  a  preparation 
for  examinations,  that  at  first  I  omitted  from  this  book  all 
reference  to  the  composition  of  pharmaceutical  preparations.  But 
as  it  is  intended  not  only  as  a  text-book  for  students,  but  also  for 
the  use  of  practitioners,  I  afterwards  considered  that  it  might  be 
convenient  to  have  the  composition  of  some  pharmaceutical 
preparations,  at  least,  for  the  purpose  of  reference.  I  have  omitted 
the  composition  of  such  preparations  as  are  like  to  be  got  ready- 
made  from  a  chemist,  but  have  inserted  the  composition  of 
infusions  which  often  need  to  be  prepared  when  required.  I  have 
also  given  the  composition  of  various  compound  pills,  but  only 
for  the  purpose  of  reference. 

In  consequence  of  this  change  in  the  plan  of  the  work  while  it 
was  passing  through  the  press,  the  preparations  of  rhubarb  have 
been  omitted  from  their  proper  place  at  page  924,  and  are  to  be 
found  at  page  1005. 

In  the  preparation  of  this  work  I  have  to  acknowledge  my 


xviii  PREFACE   TO  THE  FIRST'  EDITION. 

obligations  to  the  admirable  works  of  Bartholow,  Binz,  Buchheim, 
Dujardin-Beaumetz,  Edes,  Husemann,  Nothnagel  and  Bossbach, 
Binger,  Schmiedeberg,  and  H.  C.  Wood.  Messrs.  Chapman, 
Soutter,  Spencer,  Spry,1  Steinthal,  Stubbs,  Walsh,1  Wells,  and 
Wright  for  the  excellent  notes  they  took  of  my  lectures;  to 
Dr.  D'Arcy  Power  for  the  verification  of  references ;  to  Dr. 
Mitchell  Bruce,  Mr.  T.  W.  Shore,  and  Mr.  H.  W.  Gardner  for 
much  kind  assistance  in  the  preparation  of  the  work,  and  to 
Prof.  Matthew  Hay,  of  Aberdeen,  whose  criticisms  and  suggestions 
have  been  invaluable.  To  Dr.  Francis  H.  Williams,  of  Boston, 
Mass.,  I  am  indebted  for  the  adaptation  of  this  work  to  the 
United  States  Pharmacopoeia,  which  by  tending  to  familiarise 
medical  men  on  each  side  of  the  Atlantic  with  the  preparations 
employed  in  both  countries  may,  I  trust,  tend  to  facilitate  the 
introduction  of  an  International  Pharmacopoeia. 

T.  LAUDEE  BBUNTON. 

March,  1885. 

1  These  names  were  inadvertently  omitted  in  the  preface  to  the  first  edition, 
but  were  mentioned  in  the  preface  to  the  second. 


Articles  and  Preparations  included  in  the  British  Pharma- 
copoeia of  1885,  which  were  not  in  that  of  1867  nor 
in  the  '  Additions  '  of  1874. 


Acidum  Borieum. 

Acidum  Carbolicum  Liquefactum. 

Acidum  Chromicum. 

Acidum  Hydrobromicum  Dilutum. 

Acidum  Lacticum. 

Acidum  Lacticum  Dilutum. 

Acidum  Meconicum. 

Acidum  Oleicum. 

Acidum  Phosphoricum  Concentratum. 

Acidum  Salicylicum. 

Alcohol  Ethylicum. 

Aloin. 

Anisi  Fructus. 

Anisi  Stellati  Fructus. 

Apomorphinse  Hydrochloras. 

Aqua  Anisi. 

Argeuti  et  Potassii  Nitras. 

Arseuii  Iodidum. 

Bismuthi  Citras. 

Bismuthi  et  Ammonii  Citras. 

Butyl-Chloral  Hydras. 

Caffeina. 

Caffeince  Citras. 

Calamina  Preparata. 

Calcii  Sulphas. 

Calx  Sulphurata. 

Chrysarobinum. 

Cimiciiugaa  Bhizoma. 

Cinchonidina  Sulphas. 

Cinchoninffi  Sulphas. 

Coca. 

Cocaine  Hydrochloras. 

Codeina. 

Collodium  Vesicans. 

Cupri  Nitras. 

Elaterinum. 

Ergotinum. 

Extractum  Belladonna?  Alcoholicum. 

Extractum  Cascarse  Sagradse. 


Extractum  Cascare  Sagradas  Liquidum. 

Extractum  Cimicifugse  Liquidum. 

Extractum  Cocse  Liquidum. 

Extractum  Gelsemii  Alcoholicum. 

Extractum  Jaborandi. 

Extractum  Bhamni  Frangule. 

Extractum  Bhamni  Frangulffi  Liquidum. 

Extractum  Taraxaci  Liquidum. 

Gelsemium. 

Glycerinum  Aluminis. 

Glycerinum  Plumbi  SubaCetatis. 

Glycerinum  Tragacanthas. 

Inf  usum  Jaborandi. 

Injectio  Apomorphinse  Hypodermica. 

Injectio  Ergotini  Hypodermica. 

Iodoformum. 

Jaborandi. 

Lamella;  Atropine. 

Lamella?  Cocaine. 

Lamellse  Physostigmine. 

Liquor  Acidi  Chromici. 

Liquor  Ammonii  Acetatis  Fortior. 

Liquor  Ammonii  Citratis  Fortior. 

Liquor  Arsenii  et  Hydrargyri  Iodidi. 

Liquor  Calcii  Chloridi. 

Liquor  Ferri  Acetatis. 

Liquor  Ferri  Acetatis  Fortior. 

Liquor  Ferri  Dialysatus. 

Liquor  Morphine  Bimeconatis. 

Liquor  Sodii  Ethylatis. 

Lupulinum. 

Menthol. 

Morphine  Sulphas. 

Oleatum  Hydrargyria 

Oleatum  Zinoi. 

Oleo-Besina  Cubebe. 

Oleum  Eucalypti. 

Oleum  Pini  SyWestris. 

Oleum  Santali. 


XX 


AETICLES  ADDED  AND   OMITTED. 


Paraffinum  Durum. 

Paraffinum  Molle. 

Physostigmina. 

Pilocarpine  Hydrochloras. 

Potassii  Cyanidum. 

Quininas  Hydrochloras. 

Ehamni  Frangulas  Cortex. 

Ehamni  Purshiani  Cortex. 

Salicinum. 

Sodii  Bromidum. 

Sodii  Iodidum. 

Sodii  Salicylas. 

Sodii  Sulphis. 

Sodii  Sulphocarbolas. 

Sodium. 

Spiritus  ^Etheris  Compositus. 

Spiritus  Cinnamomi. 

Staphisagrias  Semina. 

Suppositoria  Iodoform!. 

Tabellaj  Nitroglycerin!. 


Thymol. 

Tinctura  Chloroformi  et  Morphinsa. 

Tinctura  Cimicifugse. 

Tinctura  Gelsemii. 

Tinctura  Jaborandi. 

Tinctura  Podophylli. 

Trochisci  Acidi  Benzoici. 

Trochisci  Santonini. 

Unguentum  Acidi  Borici. 

TJnguentum  Acidi  Carbolici. 

Unguentum  Acidi  Salicylici. 

Unguentum  Calamines. 

Unguentum  Chrysarobini. 

Unguentum  Eucalypti. 

UnguentumHydrargyriNitratisDilutum. 

Unguentum  Iodoformi. 

Unguentum  Staphisagrise. 

Unguentum  Zinci  Oleati. 

Vapor  Olei  Pini  Sylvestris. 

Zinci  Sulphocarbolas. 


Articles  and  Preparations  included  in  the  British  Pharma- 
copeia or  1867  or  in  the  '  Additions  '  of  1874,  but 
omitted  in  the  British  Pharmacopoeia  of  1885. 


Areca. 

Cadmii  Iodidum. 

Castoreum. 

Decoctum  Ulmi. 

Digitalmum. 

Dulcamara. 

Enema  Tabaci. 

Ferri  Iodidum. 

Ferri  Oxidum  Magneticum. 

Ferri  Peroxidum  Humidum. 

Hydrargyri  Iodidum  Viride. 


Infusum  Dulcamaras. 
Liquor  Atropia. 
Mistura  Gentianse. 
Pilula  Quinias. 
Ehamni  Succus. 
Sodas  Acetas. 
Stramonii  Folia. 
Syrupus  Bhamni. 
Tinctura  Castorei. 
Ulmi  Cortex. 
Unguentum  Cadmii  Iodidi. 


Articles  and  Preparations  the  Names  of  which  have 
been  altered. 


Former  Names,  1867  or  1874. 
Aconitia 

Albumen  Ovi        .        . 
Ammonias  Benzoas        . 
Ammoniae  Carbonas 
AmmonisB  Nitras  . 
Ammoniae  Phosphas 
Arnicas  Badix 


Present  Names,  1885. 
Aconitina. 
Ovi  Albumen. 
Ammonii  Benzoas. 
Ammonii  Carbonas. 
Ammonii  Nitras. 
Ammonii  Phosphas. 
Arnicas  Bhizoma. 


ALTERATIONS  OF  NAME. 


xxi 


Former  Names,  1867  or  1874. 
Assafostida    . 
Atropia 

Atropias  Sulphas  . 
Berberies  Sulphas 
Calcis  Carbonas  Prsecipitata 
Calcis  Hydras 
Calcis  Hypophospliis     . 
Calcis  Phosphas    . 
Calx  Chlorata 
Canellas  Alba?  Cortex    . 
Caidp.momura 
Cataplasma  Sodas  Chloratas 
Catechu  Pallidum 
Cinchonas  Flavas  Cortex 
Cinchonas  Pallidas  Cortex 
Decoctum  Cinchonas  Flavas 
Ecbalii  Fructus     . 
Emplastrum  Cerati  Saponis 
Enema  Assafoetidas 
Enema  Magnesia?  Sulphatis . 
Extractum  Cinchonas  Flavas 
Ferri  et  Ammonia  Citras 
Ferri  et  Quinias  Citras  . 
Hydrargyri  Sulphas 
Infusum  Cinchonas  Flavas 
Liquor  Ammonias  Acetatis 
Liquor  Ammonias  Citratis 
Liquor  Atropias  Sulphatis 
Liquor  Bismuthi  et  Ammonias  Citratis 
Liquor  Calcis  Chlorates 
Liquor  Magnesias  Carbonatis 
Liquor  Magnesias  Citratis 
Liquor  Morphias  Acetatis 
Liquor  Morphias  Hydrochloratis 
Liquor  Potasses  Pcrmanganatis 
Liquor  Sodas  Arseniatis 
Liquor  Sodas  Chloratas  . 
Liquor  Strychnias 
Lithias  Carbonas  . 
Lithias  Citras 


Liquidum 


Magnesias  Carbonas 
Magnesias  Carbonas  Levis 
Magnesias  Sulphas 
Morphias  Acetas    . 
Morphias  Hydrochloras 
Physostigmatis  Faba    . 
Pilula  Aloes  et  Assafoetidas 
Pilula  Assafcetidas  Composita 
Podophylli  Badix 
Potasses  Acetas 
Potassas  Bicarbonas 
Potassee  Bichromas 


Present  Names,  1883. 
Asafostida. 
Atropina. 
Atropines  Sulphas. 
Beberinas  Sulphas 
Calcii  Carbonas  Precipitata. 
Calcii  Hydras. 
Calcii  Hydrophosphis, 
Calcii  Phosphas. 
Calx  Cblorinata. 
Canellas  Cortex. 
Cardamomi  Semina. 
Cataplasma  Sodas  Chlorinates. 
Catechu. 

Cinchonas  Cortex. 
Cinchonas  Cortex. 
Decoctum  Cinchonas  [Bubras], 
Ecballii  Fructus. 
Emplastrum  Saponis  Fuscum. 
Enema  Asafostidas. 
Enema  Magnesii  Sulphatis. 
Extractum  Cinchonas  [Bubras]  Liquidum. 
Ferri  et  Ammonii  Citras. 
Ferri  et  Quinines  Citras. 
Hydrargyri  Persulphas. 
Infusum  Cinchonas  [Bubras]  Acidum. 
Liquor  Ammonii  Acetatis. 
Liquor  Ammonii  Citratis. 
Liquor  Atropines  Sulphatis. 
Liquor  Bismuthi  et  Ammonii  Citratis. 
Liquor  Calcis  Chlorinates. 
Liquor  Magnesii  Carbonatis. 
Liquor  Magnesii  Citratis. 
Liquor  Morphinas  Acetatis. 
Liquor  Morphines  Hydrochloratis. 
Liquor  Potassii  Permanganatis. 
Liquor  Sodii  Arseniatis. 
Liquor  Sodas  Chlorinate. 
Liquor  Strychninas  Hydrochloratis. 
Lithii  Carbonas. 
Lithii  Citras. 
Magnesia  Ponderosa. 
Magnesii  Carbonas  Ponderosa. 
Magnesii  Carbonas  Levis. 
Magnesii  Sulphas. 
Morphinas  Acetas. 
Morphinas  Hydrochloras. 
Phosostigmatis  Semen. 
Pilula  Aloes  et  Asafcetidte. 
Pilula  Asafoetidas  Composita. 
Podophylli  Bhizoma. 
Potassii  Acetas. 
Potassii  Bicarbonas. 
Potassii  Bichromas. 


xxii  ALTERATIONS  AND  SUBSTITUTIONS. 

Former  Names,  1867  or  1874.  Present  Names,  1885. 

Potasss  Carbonas         ....  Potassii  Carbonas. 

Potassse  Chloras Potassii  Chloras. 

Potassae  Citras Potassii  Citras. 

Potassse  Nitras      .....  Potassii  Nitras. 

Potasss  Permanganas  ....  Potassii  Permanganas. 

Potassse  Prussias  Flava         .        .        .  Potassii  Ferrocyanidum. 

Potassse  Sulphas Potassii  Sulphas. 

Potassse  Tartras Potassii  Tartras. 

Potassse  Tartras  Acida  ....  Potassii  Tartras  Acida. 

Quinife  Sulphas Quininse  Sulphas. 

Serpentarise  Radix        ....  Serpentarise  Ehizoma. 

Sodre  Arsenias Sodii  Arsenias. 

Sodffi  Bicarbonas Sodii  Bicarbonas, 

Sodas  Carbonas      ...         .         .         -  Sodii  Carbonas. 

Sodas  Carbonas  Exsiccata     .        .        .  Sodii  Carbonas  Exsiccata. 

Sodse  Citro-tartras  Efiervescens    .         .  Sodii  Citro-tartras  Effervescens. 

Sodas  Hypophosphis      ....  Sodii  Hypophosphis. 

Sodse  Nitras Sodii  Nitras. 

Sodas  Phosphas Sodii  Phosphas. 

Sodas  Sulphas Sodii  Sulphas. 

Sodas  Valerianas Sodii  Valerianae. 

Strychnia Strychnina., 

Suppositoria  Morphia;  ....  S.uppositoria  Morphinse. 

Suppositoria  Morphise  cum  Sapone      .  Suppositoria  Morphinse  cum  Sapone. 

Tinctura  Assafoetidas     ....  Tinctura  Asafoetidas. 

Tinctura  Quinise Tinetirra  Quininse. 

Tinctura  Quinise  Ammoniata        .        .  Tinctura  Quininas  Ammoniata. 

Trochisci  Morphiaa        ....  Trochisci  Morphinae. 

Trochisci  Morphias  et  Ipecacuanha      .  Trochisci  Morphinse  et  Ipecacuanb.se. 

Trochisci  Potassse  Chloratis .         .         .  Trochisci  Potassii  Chloratis. 

Trochisci  Sodse  Bicarbonatia         .        .  Trochisci  Sodii  Biearbonatis. 

Unguentum  Aconitiae    ....  Ungue,ntum  Aconitinas. 

Unguentum  Atropise     ....  Unguentum  Atropines. 

Unguentum  Veratrise    ....  Unguentum  Veratrinse. 

Valerianse  Radix Valeriana}  Rhizoma. 

Vapor  Conise Vapor  Coninse. 

Veratria Veratrina. 

Veratri  Viridis  Radix    ....  Veratri  Viridis  Rhizoma. 

Vinum  Quinise      .....  Vinum  Quininse., 


Substitutions.   • 


Antimonium  Nigrum  Purificatum  for        Antimonfum  Nigrum. 
Cinchonas  Rubral  Cortex )  f  Cinchonas'  Flavas  Cortex. 


(in  preparations)  [  "       t 

Pulvis  Elaterini  Compositus  „ 

Tinctura  Cinchonas  [Rubra]  „ 
Unguentum  Glycerini  Plumbi )  f 

Subacetatis  J  "       \ 


Cinehonse  Pallidas  Cortex. 
Pulvis  Elaterii  Compositus. 
Tinctura  Cinehonse  Flavse. 
Unguentum  Plumbi  Subacetatis  Com- 
positum. 


ALTERATIONS. 


xxiu 


Pkepabations  the  Composition  op  which  has  been  altered. 


(Minor  alterations  are  not  included.) 


Acidum  Sulphurosum. 

Alumen. 

Antimqnium  Sulphuratum. 

Extractum  Cinchona  Liquidum. 

Infusum  Cinchonas  Acidum. 

Injectio  Morphine  Hypodermica. 

Liquor  Epispasticus. 

Liquor  Iodi. 

Oleum  Phosphoratum. 

Pilula  Phosphori. 

Pulvis  Glyoyrrhizse  Compositus. 


Tinctura  Quininse. 

Unguentum  Hydrargyri  Ammoniati. 

The  fatty  basis  of  the  four  suppositories 

of  B.P.  1867  is  now  oil  of  theobroma 

only. 
In  some  of  the  ointments  paraffins  have 

been  substituted  for  lard. 
Scammony  Besin  has  been  substituted 

for  Scammony  in  most  preparations 

of  Scammony. 


The  strengths  of  the  following  preparations  have  been  altered  from  1  in  109 

to  1  m  100. 


Liquor  Arsenicalis. 
Liquor  Arsenici  Hydrochloricus. 
Liquor  Atropine  Sulphatis. 
Liquor  Morphine  Acetatis. 


Liquor.  Morphine  Hydrochloratis. 
Liquor  Potassii  Permanganatis. 
Liquor  Sodii  Arseniatis. 
Liquor  Strychnine  Hydrochloratis. 


CONTENTS. 


PAGE 

INTRODUCTION 3 


SECTION  I. 
GENEKAL  PHAEMACOLOGY  AND  THEEAPEUTICS. 

CHAPTER  I. 

General  Relations  between  the  Okganish  and  Substances  Affecting:  it, 

pp.  9-32. 

List  of  Elements . , 9 

Nature  of  Elements 11 

Classification  of  Elements        .        .        .        .        .        ...        .        •        .15 

Mendelejeff's  Classification  of  the  Elements 19 

Organic  Radicals 20 

Chemical  Reactions  and  Physiological  Reactions 24 

Relation  between  Isomorphism  and  Physiological  Action        ....  26 

„            „       Spectroscopic  Characters  and  Physiological  Action .        .    .  27 

„           „      Atomic  Weight  and  Physiological  Action     .        ...  28 

Connection  between  Chemical  Constitution  and  Physiological  Action         .   .  30 

CHAPTER  H. 

Circumstances  which  Affect  the  Action  of  Dbuos  on  the  Obganism, 
pp.  33-56. 

Local  and  Remote  Action         .        .        . 33 

Interaction  of  Various  Functions 33 

Direct  and  Indirect  Action '     .  -     . 34 

Selective  Action  of  Drugs     .        . 34 

Primary  and  Secondary  Action  -     .  • 35 

Relation  of  Effect  to  Quantity  of  the  Drag 36 

Homoeopathy    ....  ........       36 

Dose     ...-.■ .37 

Size ..  •'.*..        •»«••■«        .37 

Mode  of  Administration    "', 38 

Absorption  of  Drugs         .        .        .        >        .        .        .        .        .        .        .39 

Duration  of  Action      •       .       .-•<>.        . 41 


xxyi  CONTENTS. 

PAGE 

Cumulative  Action 41 

Effect  of  Different  Preparations 42 

„        Fasting 43 

„        Conditions  of  the  Stomach 43 

Habit 43 

„        Temperature '44 

„        Climate 48 

Time  of  Day 48 

„        Season 48 

„        Disease 49 

Use  of  Experiments         .  • 49 

Comparative  Pharmacology 50 

Idiosyncrasy 51 

Experiments  upon  Healthy  Men 51 

Fallacies  of  Experiment  upon  Man 52 

Experiments  in  Disease 52 

Objections  to  Experiment 53 

Erroneous  Deductions  from  Experiments 55 


CHAPTEE  HI. 

Action  op  Dhugs  on  Protoplasm,  Blood,  and  Low  Organisms,  pp.  57-108. 

Action  of  Drugs  on  Albumin 57 

„             „             Protoplasmic  Movements 59 

Method  of  Experimentation     .  ■      .  •      .        .        .  ^      .  -      .  -      .        .        .  59 

Amoeba        .        . .      . .       .        .        .  •      .  -      .  -      . .      .  •      .        .        .    .  60 

Leucocytes       .■.>.-,        .  •      .        .  • 61 

Effect -of  Drugs  on  leucocytes     .  ■               61 

Movements  of  Leucocytes  in  the  Blood-vessels 62 

,i             Bed  Blood  Corpuscles 63 

Action'  of  Drugs  on  Infusoria 63 

Relations  of  Motion  and  Oxidation 65 

Oxidation  of  Protoplasm 67 

Oxygen-carrying  Power  of  Protoplasm    • 68 

Ozonising  Power  of  Protoplasm 69 

Aotion  of  Drugs  on  Oxidation 69 

Seduction  by  Protoplasm 70 

Action  of  Drugs  on  Blood 70 

Catalysis— Fermentation— Inorganic  Ferments 73 

Ferments,  Organic  and  Organised    .        . '  * ' 74 

Action  of  Drugs  on  Enzymes  .        .        . 76 

^yjnogens 80 

Organised  Ferments         .._..,.,., 80 

leasts  .        .        ....  ^     .,     ...  , 81 

Moulds     .        .,.,.,.,;>..,.. 82 

Bacteria               ..,.,.,., 82 

Struggle  for. Existence, between  the  Organism  and  Microbes    •  ,     .       ..        .  85 

Action  of  Drugs  on  the  Movenjents.of  Bacteria   ■  ..,.,.,.,.,.  88 

■    „  „        ,    Reproduction  of  Bacteria  .,.,.,.,.        .        .89 

it            »            ,        .  »t     .        ,        ii        Mode  of  Experimenting  on   .    .  89 

„    ,       i,        ,   Particular  Species, of  Bacilli ,.,.,.        .  .92 

l',n    .       >•            .        ,  ii     .        ,        .«          Mode  of, Experimenting  on    .  92 


CONTENTS.  xxvii 

PAGE 

Action  of  Drugs  on  Development  and  Growth  of  Bacilli 95 

Influence  on  Antiseptics  of  the  Solvent 96 

„              „              „        Admixture 96 

„              „              „        Temperature        .        .        •        .        .        .    .  96 

.  Alterations  in  Bacteria  by  Heat  and  Soil 96 

Possible  Identity  of  different  Forms,  of  Bacteria 97 

Action  of  Bacteria  and.  their  Products  on  the  Animal  Body    ....  98 

Alkaloids  formed  by  Putrefaction — Ptomaines 99 

,,                „                  „              Leucomaines 101 

Effect  of  Drugs  on  the  Action  of  Bacteria  in  the  Animal  Body    .        .        .    .  102 

Antiseptics — Antizymotics— Disinfectants — Deodorizers         ....  103 

Uses  of  Antiseptics 104 

Disinfectants 106 

,  Deodorizers 106 

Antiperiodics 107 


CHAPTER  IV. 

Action  of  Drugs  on  Invertebbata,  pp.  109-116. 

Action  of  Drugs  on  Medusae 109 

„.    .       „  Mollusca 114 

„•        ■  „  Ascidians 114 

,  Annnlosa 114 


.     CHAPTEB  V. 
Action  of  Drugs  on  Muscle,  pp.  117-143. 

Action  of  Drugs  on  Voluntary  Muscle 117 

Irritability  of  Muscle        .        .' 119 

Contraction  of  Muscle .        .        ; 119 

Latent  Period  of  Muscle  . 120 

Summation  of  Stimuli 122 

Contraction  of  Muscle 122 

Fatigue         .....        f 123 

Contracture 124 

Tetanus        :                         12S 

'Muscular  Poisons     .'       .'        .'        .        .'        .'        .'        .'        ."    '    .        .        .  126 

Massage 131 

Propagation  of  the  Contraction  Wave  in  Muscle  ; 131 

Rhythmical  Contraction  of  Muscle      .        .        . 131 

Pathology  of  Tremor .        .        .        .  133 

Treatment  of,  Tremcr  .,        ..        ..        ..        ..        . 13ft 

Connection  between.  Chemical  Constitution  and   Physiologjpal  Action  on, 

Muscle  .".*,.' .        *        .        .        .13.4 

Action  of  Drugs,  on  Muscle  is  Relative  and  not  Absolute      .        .        .        .    .  136 

„           „         on  Involuntary  Muscular  Fibre .  137 

Effect  of  Stimuli .138 

Relation  of  Contractile  Tissue  to  the  Nerves    .......  139 

Propagation  of  Contraction  Waves .    .  139 

Artificial  Bhvthm,   .......        . 140 

Hypothetical  Considerations  regarding  the  Action  of  Drugs  on  Muscle       .   .  141 


xxviii  CONTENTS. 

CHAPTER  VI. 
Action  op  Drugs  on  Nerves,  pp.  144-158* 

FAGS 

General  Action  of  Drugs  on  the  Nervous  System 144 

Action  of  Drugs  on  Motor  Nerves 146 

Methods  of  Experiment ....  147 

Paralysis  of  Motor  Nerve-Endings  by  Drugs 147 

Advantage  of  the  Method  of  Local  Protection 149 

Paralysers  of  Motor  Nerves 150 

Exact  Localisation  of  the  Action  of  Curare 1S1 

Action  of  Drugs  in  Increasing  Excitability  of  Motor  Nerves        .        .        .    .  153 

Irritation  of  Motor  Nerve-Endings    .        .                154 

Action  of  Drugs  on  the  Trunks  of  Motor  Nerves 154 

,,             „             Sensory  Nerves 155 

Local  Sedatives  and  Local  Ansssthetics 157 

Stimulating  Action  of  Drugs  on  the  Peripheral  Ends  of  Sensory  Nerves .        .  157 

CHAPTER  VII. 
Action  of  Drugs  on  the  Spinal  Cord,  pp.  159-182. 

Action  on  the  Conducting  Power  of  the  Cord 159 

Action  of  Drugs  on  Reflex  Action    . 163 

Direct,  Indirect,  and  Inhibitory  Paralysis  of  the  Spinal  Cord  by  Drugs       .    .  164 

Indirect  Paralysis 164 

Direct           ,,                 164 

Spinal  Depressants  and  their  Uses 165 

Inhibitory  Paralysis 165 

Nature  of  Inhibition 167 

Interference  in  Nervous  Structures 169 

Effect  of  Altered  Rate  of  Transmission 169 

Opposite  Conditions  produce  Similar  Effects 170 

The  Same  Conditions  may  cause  Opposite  Effects 170 

Stimulation  and  Inhibition  merely  Consequences  of  Relation      .        .        .    .  170 

Test  of  the  Truth  of  the  Author's  Hypothesis  regarding  Inhibition         .        .  171 

Explanation  of  the  Action  of  Certain  Drugs  on  this  Hypothesis  .        .        .    .  171 

Stimulating  Action  of  Drugs  on  the  Reflex  Powers  of  the  Cord        .        .        .  177 

Localisation  of  the  Action  of  Strychnine  by  Magendie 177 

Spinal  Stimulants    .        .        .        . 181 

CHAPTER  VHI. 

Action  op  Drugs  on  the"  Brain,  pp.  183-215. 

Functions  of  the  Brain  in  the  Frog 183 

„  „  „  Mammals .184 

Depressant  Action  of-  Drugs  on  Motor  Centres  in  the  Brain         .        .        .    .  187 

Irritant             „                             „                            „                    ....  188 

Convulsions 188 

Action  of  Drugs  on  the  Sensory  and  Psychical  Centres  in  the  Brain        .        .  191 

Drugs  which  Increase  the  Functional  Activity  of  the  Brain         .        ,        .    .  192 

Nerve  Stimulants 192 

Cerebral  Stimulants     ....                 192 

Drugs  which  Lessen  the  Functional  Activity  of  the  Brain      .                       .  195 


CONTENTS.  xxix 

PAGE 

Hypnotics  or  Soporifics 196 

Narcotics 200 

Anodynes  or  Analgesics 201 

Adjuncts  to  Anodynes 203 

Anaesthetics 203 

Stages  of  their  Action 206 

Uses  of  Anaesthetics 207 

Dangers  of  Anesthetics 207 

Mode  of  Administering  Anesthetics 209 

Anesthesia  in  Animals 210 

History  of  the  Discovery  of  Anesthesia        .        .        . 21] 

Antispasmodics 212 

Action  of  Drugs  on  the  Cerebellum 215 

CHAPTBE   IX. 
Action  of  Drugs  on  the  Okoans  of  Special  Sense,  pp.  216-231. 

Action  of  Drugs  on  the  Eye 216 

„            „            „     Conjunctiva 216 

„            „            „     Lacrimal  Secretion 217 

Projection  of  the  Eyeball 217 

Action  of  Drugs  on  the  Pupil 217 

„            „            „     Accommodation 223 

„            „            „     Intra-ocular  Pressure  .        , 224 

Uses  of  Mydriatics  and  Myotics 225 

Action  of  Cocaine 226 

Action  of  Drugs  on  the  Sensibility  of  the  Eye 227 

„            „       in  Producing  Visions 228 

„             „       on  Hearing: 228 

„            „       on  Smell 280 

„             „       on  Taste   .         .         ...         . 230 

CHAPTEB  X. 
Action  of  Dbucs  on  Respiration,  pp.  232-261. 

Eespiratory  Stimulants  and  Depressants 232 

Comparative  Anatomy  of  the  Eespiratory  Centre 232 

Action  of  Drugs  on  the                   „                „ 240 

„            „            „      Eespiratory  Nerves 244 

Sternutatories  or  Errhines 245 

Pulmonary  Sedatives 246 

Pathology  of  Cough 247 

Eemedies  which  Lessen  Irritation 249 

Pulmonary  Sedatives 250 

Expectorants .  250 

Action  of  Drugs  on  the  Bronchial  Secretion .  252 

„             „             „      Expulsive  Mechanism      ......  254 

Adjuncts .        .  255 

Arrest  of  Colds     .        . '.        .        .    .  '256 

Selection  of  Eemedies  in  Treatment  of  Cough 257 

Action  of  Drugs  on  the  Bronchi '259 

Pathology  of  Bronchial  Asthma 259 

Treatment  of        „              „                 . 260 


xxx  CONTENTS. 

CHAPTER  XI. 
Action  of  Detjos  on  the  Circulation,  pp.  262-339. 

FAGB 

Arteries  and  Veins •  262 

Blood-pressure 263 

Painting  and  Shock ' 264 

Scheme  of  the  Circulation 265 

Circulation  in  the  Living  Body 267 

Mode  of  Ascertaining  the  Blood-pressure 268 

Fallacies 269 

Alterations  in  Blood-pressure       .        .     — 270 

Belation  of  Pulse-rate  and  Arterioles  to  Blood-pressure 271 

Effect  of  the  Arterioles  on  Pulse  Curves 275 

Investigation  of  the  Action  of  Drugs  on  the  Arterioles     .....  277 

Method  of  Measurement  by  Bate  of  Flow 281 

Action  of  Drugs  on  Vaso-motor  and  Vaso-dilating  Nerves       ....  283 

Action  of  Other  Parts  on  the  Blood-pressure 285 

Keflex  Contraction  of  Vessels  .        .        .        .' 285 

Action  of  Drugs  on  Reflex  Contraction  of  Vessels 286 

.  Comparative  Effect  of  Heart  and  Vessels  on  Blood-pressure  in  Different 

Animals 287 

Influence  of  Nerves  on  Blood-pressure 289 

Action  of  the  Heart  on  Blood-pressure 292 

Causes  of  Alteration  in  Blood-pressure  and  Pulse-rate 293 

Effect  of  Drugs  on  the  Pulse-rate •        .        .        .  295 

Action  of  Drugs  on  the  Cardio-inhibitory  Action  of  the  Vagus     .        .        .    .  295 

Keflex  Stimulation  of  the  Vagus 296 

Causes  of  Quickened  Pulse 297 

Action  of  Drugs  on  Vagus-Koots 297 

Action  on  Accelerating  Nerves 298 

Stimulating  Effect  of  Asphyxial  Blood  on  the  Medulla 298 

Stimulation  of  the  Heart  by  Increased  Blood-pressure 298 

Palpitation 299 

The  Heart  of  the  Frog 299 

Action  of  Drugs  on  the  Heart  of  the  Frog 301 

„              „          its  Muscular  Substance 305 

Differences  between  the  Heart  Apex  and  the  Heart 308 

Action  of  Drugs  on  the  Vagus  of  the  Frog 310 

Action  of  Drugs  on  Inhibition  of  the,  Heart 310 

Theories  Regarding  the  Mode  of  Action  of  Drugs  on  the  Heart   .        .        .    .  312 

Drugs  which  Act  on  the  Cardiac  Muscle 316 

„            „            „       Motor  Ganglia .  316 

„             „             .,       Inhibitory  Ganglia 317 

„            „            „       Vagus-Ends  in  the  Heart 317 

„            „            .,       Vagus-Centre 317 

„            „            „       Accelerating  Centre 318 

,,            »            ..       Capillaries 318 

„            „            „       Vaso-motor  Nerves 318 

>•             ..             ..                ..           Centre     .                  319 

Stannius's  Experiments ...  319 

General  Considerations  regarding  the  Heart    .                 322 

Regulating  Action  of  the  Nervous  System    .                                         v  324 


CONTENTS.'  xxxi 

l'AGE 

Hypothesis  regarding  the  Action  of  .the  Vagus 325 

Inhibition  in  the  Heart        *        ..        .  -.    .  326 

Therapeutic  Uses  of  Drugs  acting  on  the  Circulation      .....  328 

Cardiac  Stimulants      .  328 

Vascular 330 

Cardiac  Tonics 331 

Bisks  attending  the  Administration  of  Digitalis  and  other  Cardiac  Tonics      .  335 

Vascular  Tonics   . 335 

Pathology  of  Dropsy 336 

Cardiac  Sedatives         . 338 

Vascular       „ 339 

CHAPTER  XII. 
Remedies  Acting  on  the  Surface  op  the  Body,  pp.  340-351. 

Irritants  and  Counter-irritants 340 

Bubefacients 344 

Vesicants 345 

Pustulants 346 

Caustics 346 

Emollients  and  Demulcents 347 

Astringents 349 

Styptics   .  350 

CHAPTEE  XHI. 
Action  op  Dbugs  on  the  Digestive  System,  pp.  352-409. 

Action  of  Drugs  on  the  Teeth 352 

„  „  „      Salivary  Glands 353 

Sialagogues 353 

„      Keflex 357 

„      Mixed 357 

„      Specific 357 

Excretion  by  the  Saliva 358 

Refrigerants 360 

Pathology  of  Thirst 360 

Anti-sialics 360 

Action  of  Drugs  on  the  Stomach 361 

Gastric  Tonics 361 

Appetite • 362 

Action  of  Drugs  on  Secretion  in  the  Stomach  . 363 

„  „  the  Movements  of  the  Stomach 365 

Absorption  from  the  Stomach 368 

Antacids 369  ^ 

Emetics 370 

Anti-emetics  and  Gastric  Sedatives 376 

Carminatives 378 

Action' of  Drugs  on  the  Intestines     .  .        .        .        .        .        .    .  379  V 

Intestinal  Movements  and  Secretion 379 

Paralytic  Secretion 380 

Constipation 384 

Action  of  Drugs  On  Absorption  from  the  Intestines      .        .        .        .        .    .  386 

Intestinal  Astringents 387 


xxxii  CONTENTS. 

PAGB 

Purgatives 389 

Action  of  Purgatives 390 

Uses  of  Purgatives 394  ' 

Action  of  Irritant  Poisons 395 

Peculiarities  in  the  Action  of  different  Irritant  Poisons       ,  .        .    .  397 

Secondary  Effects  of  Irritant  Poisoning 398 

Action  of  Drugs  on  the  liver .  399 

Hepatic  Stimulants 402 

Cholagogues 404 

Adjuncts  to  Cholagogues 406 

Uses  of  Hepatic  Stimulants  and  Cholagogues 407 

Hepatic  Depressants 407 

Action  of  Drugs  on  the  Pancreas 407 

Anthelmintics 408 


CHAPTER   XIV. 
Drugs  Acting  on  Tissue-Change,  pp.  410-421. 

Tonics 410 

Hasmatinics 412 

Alteratives 413 

Antipyretics — Febrifuges '.  ....  416 

CHAPTER  XV. 
Action  or  Drugs  on  Excretion,  pp.  422-446. 

Action  of  Drugs  on  the  Kidneys         .         .         . 422 

Circumstances  Modifying  the  Secretion  of  Urine 427 

Mode  of  Action  of  Diuretics         .  , 431 

Adjuvants  to  Diuretics 434 

Action  of  Drugs  on  Albuminuria 434 

Lithontriptics 436 

Action  of  Drugs  on  the  Skin 437 

Diaphoretics  and  Sudorifics .        .        .  437 

Excretion  by  the  Sweat  Glands    .  , 439 

Relation  between  Sweat  Glands  and  Kidneys  .    ,  ...  439 

Action  of  the  Skin  in  Regulating  Temperature  .        .  .    .  440 

Antihidrotics  or  Anhidrotics 441 

Pathology  of  Night  Sweats  .  ...  442 

Action  of  Drugs  on  the  Bladder 443 

Urinary  Sedatives  and  Astringents 445 


CHAPTER  XVI. 
•  Action  of  Drugs  on  the  Generative  System,  pp.  447-456. 

Aphrodisiacs  and  Anaphrodisiacs 447 

Aphrodisiacs 449 

Anaphrodisiacs 457 

Emmenagogues 452 

Ecbolics 454 

Action  of  Drugs  upon  the  Mammary  Glands 455 


CONTENTS.  xxxiii 

43HAPTBE  XVTT. 
Methods  of  AnMiNisiEEiNa  Dkugs,  pp.  457-485. 

RAGE 

Application  of  Drugs  by  the  Skin 457 

Epidermic  Application       " 457 

Baths      .        . ' 459 

Cold  Bath    .                       * 460 

»    Pack 463 

„    Sponging 463 

„    Douches                            .    ' 463 

Local  Application  of  Cold  •  .■  .     .        .        .        .        .        .        .'-      .        .    .  464 

Cold  Sitz  Bath 464 

„    Foot  Bath 464 

„    Compresses      .        .        .     ' 464 

Tepid  Baths         .        .        .        .....        .- 466 

Warm 466 

Hot        „              467 

„    Foot  Bath 467 

„    Sitz  Bath 467 

Poultices 468 

Medicated  Baths  .        .      - 469 

Sea-bathing     .        .        .'       .        . 469 

Carbonic-acid  Bath 469 

Acid  Bath 469 

Alkaline  Bath 470 

Sulphurous  Bath 470 

Mustard  Bath , 470 

Pine  Bath 470 

Vapour  Baths 470 

Calomel  Fumigation , .        .        .        .  471 

Air  Baths— Turkish  Bath 471 

Friction  and  Inunction 472 

Massage 472 

Inunction 473 

Endermic  Application  of  Drugs 474 

Hypodermic  Administration  of  Drugs 474 

Objections  to  Hypodermic  Injections .        .    .  476 

Application  of  Drugs  to  the  Eye      .        .       . .        .       . .        .        .        .        .  477 

Ear, 477 

<>                   >•                 Nose 478 

1.                   »                 Larynx 479 

»                   „                 Lungs  . 481 

„                  „                Mouth  and  Pharynx       . . 482 

Masticatories — Gargles 482 

Application  of  Drugs  to  the  Stomach  .        .        ...        .        .        .        .    .  482 

Stomach-pump 483 

Gastric  Syphon 483 

Application  of  Drugs  to  the  Intestine 484 

Enemata      . .        .        .        .        .    .  484 

Suppositories 484 

Application  of  Drugs  to  the  Urethra 484 

„                  „                Vagina  and.Uterus       .        .     '  .        .        .        .  485 

b 


xxxiv  CONTENTS. 

CHAFTEB  XVHL 

Antidotes,  pp.  486-491. 

PASS 

Antidotes  to  Poisonous  Gases 486 

Acids 487 

Alkalies 487 

„  Alkaloids,  &e. 488 


CHAPTEK  XIX. 

Antagonistic  Action  or  Deugs,  pp.  492-496. 

OHAPTEE  XX. 
Dosage,  p.  497. 


SECTION  n. 

GENEEAL  PHAEMACY. 

CHAPTEE  XXI. 

Pharmaceutical  Peepaeations,  pp.  501-534. 

Abstracta — Abstracts .  503 

Aceta  —Vinegars 503 

Alkaloidea — Alkaloids 503 

Aquffi — Waters .  505 

Gataplasmata — Poultices 506 

Cerata — Cerates .        .        .        .        .        .    .  506 

Chartse  —Papers 506 

Collodia — Collodions 507 

Confectiones — Confections— Electuaries  ........  507 

Decocta — Decoctions 507 

Elixiria— Elixirs 508 

Emplastra— Plasters 508 

Enemata — Injections — Enemas — Clysters 508 

Essentia — Essences 509 

Extracta — Extracts 509 

Glycerina— Glycerita — Glycerines 513 

Infusa — Infusions 513 

Injectiones  Hypodermics — Hypodermic  Injections 514 

Lamellte— Gelatine  Discs 515 

Linimenta — Liniments — Embrocations 515 

Liquores— Solutions         .        , 517 

Lotiones — Lotions 518 

Masses— Masses 518 

Mellita — Honeys 518 

Misturse — Mixtures .  513 

Mueilagines — Mucilages       .        .        ...        .        ...         .        .    ,  519 


.-CONTENDS. 


•  XXXV 


TAUK 


Olea— Oils,  Fixed  and  Volatile 61!) 

Oleata — Oleates  ...  621 

Oleoresinffi — Oleoresins 521 

Oxymel .    .  521 

PilulsB— Pills 521 

Pulveres — Powders .    .  524 

Resinae — Eesins       .•.-...        . -  524 

Spiritus — Spirits ,    .  525 

Suppositoria — Suppositories 526 

Succi — Juices       .        .        .        »   , 526 

Syrupi — Syrups 527 

Tfcbellffl— Tablets 528 

TifcctursB — Tinctures 528 

Triturationes — Triturations 531 

Troehisci — Lozenges 531 

Unguent  a — Ointments 532 

Vapores — Vapours — Inhalations 533 

Vina— Wines 534 


■     SECTION  m. 

INOEGANIC  MATEEIA  MEDICA. 

CHAPTER  XXn. 
Hydhooen,  Oxygen,  Ozone,  OABBoiir,  Sulphur,  and  the  Halogens,  pp.  537-564. 

Hydrogen         .■ 537 

Oxygen 537 

Ozone      .        .  ■       .        .        ...        .        .  -       .        .        .        .        ,        .  539 

Peroxide  of  Hydrogen  .                 540 

Carbon 541 

Sulphur .543 

Sulphuretted  Hydrogen 545 

Halogen  Elements — General  Source  and  Characters    ....            .  547 

Mode  of  Preparation 548 

General  Action 549 

Chlorine • 549 

Chlorinated  Lime  -       .        .•               550 

„            Soda 551 

Bromine 552 

Bromide  of  Potassium 553 

„            Sodium 555 

„            Ammonium 556 

„            Lithium     .        .        .     ■ 556 

„           Calcium ,  556 

„            Zirio  (vide  p.  678)      .        .        .        . 556 

Iodine .        .        .        .        .  56? 

Iodide  of  Sulphur         .        » ,.        .        .        .    .  557 

Action  of  Iodine       . .        .  558 

Iodide  of  Potassium ...        .                .    .  559 


xxxvi 


CONTENTS. 


Iodide  of  Sodium ,  563 

Ammonium  .  •    •  "63 

Zinc  (vide  p.  673) 564 

Silver  (vide  p.  680) 564 

Mercury,  Bed  (vide  p.  696) 564 

„        Green  (rede  p.  ,696) fi64 

Lead  (vide  p.  705) 564 


CHAPTEB  XXHI. 
Acids,   pp.  565-591. 


General  Characters  of  Acids 
„       Preparations  of  Acids . 
„       Action  ,        „ 

Sulphuric  Acid 

Sulphurous  „ 

Hydrochloric  Acid   .     , 

Hydrobromic    „ 

Hydriodic  Acid  (Syrup) 

Nitric  „ 

Nitro-hydrochloric  Acid 

Acetic 

Phosphorio 

Tartaric 

Citric 

Oxalic 

Boric  or  Boracic 

Chromic 

Carbonic 

Hydrocyanic 

Lactic 

Oleic 

Arsenious  „     (vide  p.  719) 

Benzoic  „    ,(vide.-p.  964) 

Carbolic  „     (vifie  p.  .813). 

Chrysophanic  „    (vide  p.  909) 

Gallic  „     (vide  p.  1033) 

Pyrogallic  „    .(vide/p.  819) 

Salicylic  „     (vide  p..819) 

Tannio         „  .(vide.?.  10,31) 


565 
565 
567 
570 
571 
572 
573 
574 
574 
575 
576 
578 
580 
580 
581 
581 
582 
583 
586 
589 
590 
591 
591 
591 
591 
591 
591 
591 
591 


CHAPTER  XXIV. 
Metals,  pp.  592-643. 


General  Classification  of  the  Metals         .... 
General  Tests  fqr  Acid  Badicals  in  Metallic  Salts 
Metals  .of  the  Alkalis.    Their  Characters  and  Reactions 
General  Physiological  Action  of  the  Alkalis         .  . 

„  „  „  Alkaline,  Group  of  .Salts 

.1  ii  ,.  Chlorides    „  „ 

„  „  „  Sulphates   „  „ 


592 
593 
596 
596 
597 
599 
602 


CONTENTS. 


xxxvn 


Comparative  Action  of  the  Alkaline  Metals 

Monad  Metals,  Group  I.,  Potassium,  Sodium,  Lithium    . 

Potassium,  General  Sources  and  Eeactions  of  its  Salts 

Preparation  of  Potassium  Salts 

General  Action  of    „    *       „i 

Characters,  Actions  and  Uses  of  Offieinal  Potassium  Salts 
Sodium,  General  Sources  and  Beactions  of  its  Salts 

Preparations  of  its  Salts  . -       r 

General  Impurities,  Tests  and  Action  . 
Characters,  Actions  and  Uses  of  Sodium  Salts 
Lithium,  Sources  and  Eeactions -of  its  Salts      .        , 
Impurities,  Tests  and  General  Action  of  Lithium  Salts  . 
Characters,  Actions  and  Uses  of  Officinal  Lithium  Salts 
Monad  Metals,  Group  II.,  Ammonium  , 

Nature  of  Ammonium  Salts 

Sources  and  Beactions 

Impurities  and  Tests 

Preparation      .        .. ,. 

General  Action 

Characters,  Actions  and  Uses  of  Officinal  Ammonium  Salts 


PAGE 

.    .    602 

.    603 

.    .    603 

604 

.    .    605 

007-617 

.    .    617 

.    618 

.    .     619 

619-630 

.    .     630 

.     630 

631-633 

.     633 

.    .     633 

.     634 

.    .    634 

.     635 

635 

037-643 


CHAPTEB  XXV. 

Metals  {continued),  Class  II.,  Dyad  Metals — Gboups  I.  and  II.,  Metals  op 
the  Alkaline  Earths  and  op  the  Earths,  pp.  644-661. 

Beactions  of  the  Metals-  in  Class  H 645 

Class  II.,  Group  I.,  Metals  of  the  Alkaline  Earths 645 

General  Action  of  „     -    „  „  „        .        .        .        .        .    645 

Calcium,  Beactions,  Preparation,  Impurities  and  Tests  of  its  Salts  .         646,  647 
Characters,  Action  and  Uses  of  Officinal  Calcium  Salts  ....     647-653 

Class  II.,  Group  I.,  Appendix — Aluminium 654 

General  Sources,  Preparation,  Beactions,  Impurities  and  Tests  of  Aluminium 

Salts 654 

Characters,  Actions  and  Uses  of  Officinal  Aluminium  Salts         .        .         654-657 

Cerium,  Action  and  Uses  of  its  Oxalate 657 

Class  II.,  Group  II.,  Magnesium 658 

Sources,  Beactions  and  Preparations  of  Magnesium  Salts        ....    658 

Impurities,  Tests  and  Action  „  „  , 659 

Characters,  Actions  and  Uses  „  „  „  .        .        .     659-661 


CHAPTEB  XXVI. 

Met-als  (continued)?  The  Heavy  Metals,  Class  II.,  Gboups  lH.  and  IV., 
and  Class  IV.,  pp.  662-706. 

General  Actions  of  Heavy  Metals 662 

„  „  Class  II.,  Group  III.,  Zinc,  Copper,  Cadmium  and  Silver  .     665 

Zinc,  its  Sources,  General  Beactions  and  Preparations  of  Zinc  Salts      .        .     667 

Impurities,  Tests  and  Action  of  Zinc  Salts 668 

Characters,  Action  and  Uses  of  Officinal  Zinc  Salts         ....    669-674 

Copper,  its  Sources,  Beactions,  Impurities  and  Tests 674 

Characters,  Action  and  Uses  of  Officinal  Salts  of  Copper        .        .        .     674-676 


xxxviii  .CONTENTS. 

PAGE 

Silver,  Characters,  Action  and  Uses  of  its  Salts          ....         676-680 
Class  II.,  Group  IT.,  Mercury 680 

General  Sources  and  Eeactions  of  Salts  of  Mercury     , 

„       Impurities,  Tests  and  Action  of  Salts  of  Mercury 
Characters,  Actions  and  Uses  of  Officinal     ,,  ,,  . 

Class  IV.,  Tetrad  Metals,  Lead  and  Tin 

General  Actions 

lead,  its  Sources,  Eeactions,  Impurities         .... 

Tests  and  Action  of  Lead     ....... 

Characters,  Actions  and  Uses  of  Officinal  Salts  of  Lead . 


.    .    680 

.    681 

686-697 

.     698 

.  .  698 
.    698 

.    .    699 

702-705 


Tin,  Action  and  Uses  of  its  Chloride 706 


CHAPTER  XXVII. 

Class  V.,  Pentad  Elements — Nitrogen,  Phosphorus,  Arsenic,  Antimont, 
and  Bismuth,  pp.  707-734. 

Nitrogen  and  its  Compounds 707 

Nitrous  Oxide 708 

Phosphorus,  its  Preparation,  Characters  and  Action    ....     709,  710 

Uses  of  Phosphorus 712 

Arsenic,  its  Sources  and  Tests 712 

General  Action  of  Arsenic    . 713 

Probable  Mode  of  Action  of  Arsenic  in  Phthisis       , 717 

Characters,  Actions  and  Uses  of  Officinal  Preparations  of  Arsenic      ,         719-721 

Antimony,  its  Sources  and  Eeactions 721 

General  Action  and  Uses 722 

Characters,  Action  and  Uses,  of  its  Offioinal  Preparations        .        .        .     727-730 

Bismuth,  its  Sources  and  Eeactions 730 

General  Action  and  Uses  of  its  Salts 731 

Character,  Action  and  Uses  of  its  Officinal  Preparations      .        .        .         732-734 


CHAPTER  XXVIII. 
Metals  {contMVUed),  Class  VIII.,  Iron,  Manoanese,  pp.  735-755. 

Iron,  its  Sources  and  Eeactions 735 

Impurities,  Tests  and  Preparation  of  its  Salts 736 

General  Action               ■  .    ■    .        .        .                 .        t        t  733 
Character,  Action  and  Uses  of  its  Officinal  Preparations     .        .        .         740-752 

Manganese _  irgg 

Class  VIII.,  Group  II.,  Gold  and  Platinum _  753 

Gold,  Preparation  and  Characters  of  its  Chloride   ......  754 

Platinum,  Preparation,  Uses  and  Action  of  its  Chloride    .        ,       .        754  755 


CONTENTS.  aureix 

SECTION  IV. 
OEGANIC  MATEELA  MEDIOA. 

OHAPTEB  XXIX. 
Cabbon  Compounds — Fatty  Sebies,  pp.  759-806. 

PAGE 

Series  of  Carbon  Compounds 759 

General  Action  of  Carbon  Compounds •  760 

Bisulphide  of  Carbon 760 

Hydro-Carbons 761 

Benzin 762 

Petrolatum  (Vaseline) 763 

Paraffin,  Hard 763 

Soft ,    .  764 

Alcohols  of  the  Series  C2H,n+1OH 764 

General  Action ,    .  764 

Methyl  Alcohol 766 

Ethyl  Alcohol :  General  Sources,  Preparation  and  General  Impurities       .   .  767 

Tests  and  General  Action 767 

Effect  of  Impurities  on  its  Action ,    .  770 

Chronic  Alcoholic  Poisoning .  770 

Causes  and  Treatment  of  Alcoholism .  772 

Uses  of  Alcohol 773 

Alcohol  as  a  Stimulant        .        . 774 

Officinal  Alcoholic  Preparations 775-778 

Aldehydes,  Acetic  aldehyde  and  Paraldehyde 778 

Ketones,  Hypnone 779 

Simple  Ethers,  Ether 780-783 

Saline  Ethers  .'...' 783 

Ethereal  Oil  and  Hoffman's  Anodyne 783 

Acetic  Ether     .        .        .'.'.' 783 

Nitrites  of  Ethyl  and  Amyl .        „ 784 

Nitro-Glycerine— Tablets  of  Nitro-Glycerine 788 

Liquor  Sodii  Ethylatis  (vide  p.  619) 789 

Haloid  Compounds 789 

Bromide  of  Ethyl 789 

Iodide  of  Ethyl        .                        790 

Chloral  Hydrate,  its  Preparations  and  Characters       .        .        .        .        .   ,  790 

Its  Action .  791 

Treatment  of  Chloral  Poisoning .   .  793 

Butyl-Chloral  Hydrate 794 

Bromal  Hydrate 794 

Bichloride  of  Methylene 795 

Chloroform,  its  Preparation,  Characters,  Impurities  and  Tests    .        .        .    .  795 

Action  of  Chloroform       .        .        .        .        . 796 

Bangers  of        „ 799 

Precautions  in  using  Chloroform     . 800 

Uses  of  Chloroform      ...        .        ...        .        .        ,        .    .  802 

Iodoform . 804 

Methylal  (vide  Appendix) <•  .  806 

Urethane  (vide  Appendix) ,        .  806 

Iodol  (vide  Appendix) .    .  806 


xl  CONTENTS.' 

CHAPTER  XXX. 
Cabbon  ..Compounds — Aromatic  Sebies,  pp.  807-826. 

PAGB 

General  Chemistry  of  the  Aromatic  Series 807 

General  Action           „             „            » 811 

Carbolic  Acid 812 

Its  Action 813 

Uses   - 815 

Sodii  Sulpho-carbolas  (vide  p.  626) 817 

Zinci  Sulpho-carbolas  (vide  p.  671)          .        .        ......        •        .        •  817 

Creasote .        .    .  817 

Eesorcin 818 

Hydroquinone       .        .  •      . 818 

Pyrocatechin 819 

Pyrogallic  Acid    .        .        . 819 

Salicylic  Acid 819 

Naphthalin  .        .        . 821 

i-  aphthol.        .        .        .        i .        .        .822 

Eydrochlorate  of  Bosaniline 822 

Pyridine 823 

Chinoline 823 

Kairin 824 

Antipyrin 824 

Antifebrin        .        ...        .        .        .        .        .  , 825 

Saccharine 825 


SECTION  V. 
VEGETABLE  MATEKIA.  MEDICA, 

InteoductioN 829 

CHAPTER  XXXI. 

Sub-Kingdom  I.,  Phanebogamje. 

DlTISIOH  I.,  ANGIOSPEBMiE  ;    CLASS  I.,  I)lOOTpaiDO.NES  PoLTPETAIJE  ; 
.  SuB-J&iASS  I.,  THAT.AMTTI.OBa!,  pp.  831-875. 

Xanunculacese 831 

Aconite     .                         831 

Staphisagria .       .        .        .        . 836 

Pulsatilla 836 

Adonis  Vernalis 837 

Cimicifuga 837 

Podophyllum 838 

Hydrastis.       .        .       .      "^ 839 

Tttagnoliaceae 840 

Star-Anise — Illicium 840 

Oil  of  Anise • 840 

IHenlspermaceae 840 

Menispenmrm 840 

Calumba 840 

Pareira 841 

Picrotoxin 842- 


CONTENTS.  xli 

PACK 

Berberidaceee  .        .     *  .     •. •. 842 

Caulophyllum 842 

Papaveraceae 843 

Eoppy  Capsules 843 

Opium .         .    .  844 

Preparations  of  Opium 844 

Meconic  Aeid 846 

Morphine 846 

Apomorphine 848 

Codeine 0 849 

Action  of  Opium 851 

Diagnosis  of  Opium  Poisoning 852 

Treatment        „              „               853 

Circumstances  Modifying  the  Action  of  Opium 856 

Action  of  the  Alkaloids  of  Opium .     •  .        . 858 

Uses  of  Opium • 859 

Khceas— Bed  Poppy 862 

Sanguinaria— Blood  Boot 863 

Chelidonium — Celandine 863 

Cruciferee      .        .     • 864 

Sinapis — Mustard 864 

Armoracia — Horseradish  .     ,. 866 

Vlolarleee 866 

Viola, — Pansy ■ 866 

Canellaceae ■ 867 

CanellaAlba - 867 

Polygalaoeae     . 867 

Senega       ...     - 867 

Krameria — Bhatany 868 

Guttlferae 869 

Cambogia — Gamboge    . 869 

TernstromlacesB 869 

Tea        .      • 869 

Caffeine  .  .        .... 870 

Malvaceae 872 

Gossypiuzn — Cotton 873 

Pyroxylin— Gun  Cotton .        .    .  874 

Collodion 874 

Althaea — Marshmallow .    .  875 

Steroullaceae  (Byttneriacese) 875 

Theobroma — Cacao 875 


CHAPTBB  XXXII. 

PHANEEOGAMa:  (continued). 

Class  I.,  Dicotyledones  Poltpetal^e  ;  Sub-Class  II.,  DiscrpLORa:,  pp.  876-898. 

Xlneee    .        .        .        .    ■' 876 

Linseed— Flaxseed .        .        .    .    876 

Erytbroxyleee 877 

Coca — ^Erythroxylum - .        .        .    .    877 

Cocaine .        .        .        .        .        .        .  -  877 

Action  of  Cocaine  .        .        .        .        .        .        .        .        ,        .    .    878 


xlii  CONTENTS. 

FAGB 

Zjrgophyllaceee 880 

Guaiacum 880 

Geranlaceee •         ■  881 

Geranium — Cranesbill 881 

Rutacese ■        •  881 

Eutese 881 

Oil  of  Rue 881 

Cusparia 881 

DiosmesB 882 

Buchu    .............  882 

Xanthoxylinas 883 

Xanthoxylum — Prickly  Ash 883 

Jaborandi — Pilooarpua 883 

Pilocarpine 883 

Action  of  Pilocarpine 884 

Aurantiese 887 

Orange 887 

Oil  of  Bergamoi 889 

Lemon 890 

Bael  Fruit 891 

Simarubaceae 892 

Quassia 892 

Bnrseraceee  or  Amyridacee 893 

Myrrh ,893 

Elemi        .....'...,,...  893 

JHellaceae 894 

Azedarach 894 

lUclnese  (Aquifoliaceae) 894 

Prinos— Black  Alder         .                         894 

Celastrinae 894 

Euonymus — Wahoo 894 

Rbamnese 895 

Cascara  Sagrada — Bhamnus  Purshianus  .......  895 

Rhamuus  Frangula — Buckthorn ,  .        .    .  895 

Ampelldse  (Vitaceue) 896 

TJvse — Raisins ,  .        .        .        .        .    .  896 

Vinum  Xericum 896 

VinumRubrum .        .                 .    .  896 

Saplndaceee  ...,....•..,..  897 

Guarana , 897 

Anaoardlacese  (Torobinthacote)    .        .        .        .      , 897 

Mastiohe 897 

Rhus  Glabra — Sumach 898 

Rhus  Toxicodendron — Poison  Ivy 898 


CHAPTER  XXXIII. 

,  Phanerogams,  (continued). 

Class  I.,  Dicottledones  Polypetal^:  ;  Sub-Class  III.,  CALYorrLORai,  pp.  899-938. 

lefuminosee         .         .         .        ....        ...        .        ,         .         .     899 

Papilionacese         .        .        .        ...        .....,.,.        .    .    899 

Glycyrrhiza— Liquorice     .       .,,..,.       ,       ,        ,        .899 


CONTENTS.  xliii 

PAUE 

Scoparius — Broom 900 

Tragacanth 900 

Pterooarpus — Santalum— Bed  Sandal-wood  or  Bed  Saunders       .    .  901 

Kino 902 

Balsam  of  Peru 902 

Balsam  of  Tolu 903 

Abrus — Jequirity 903 

Physostigma — Calabar  Bean 904 

Hamatoxylon — Logwood 908 

Chrysarobinum— Chrysophaoic  Acid — Goa  Powder  ....  908 

Cffisalpinte ' 909 

Senna 909 

Cassia — Purging  Cassia 911 

Tamarind 911 

Copaiba — Copaiva 912 

Pi  scidia  Erythrina — Jamaica  Dogwood 913 

Mimoseas 913 

Acacia 913 

Catechu     , ,        .        .    .  914 

Erythrophloeum — Casca — Sassy 915 

Indigo 915 

Jtosaeese        ,         .         .         ( 915 

Prunes; 915 

Amygdala  Dulcis-^Sweet  Almond 915 

.  -    Amygdala  Amara — Bitter  Almond        ,....,.  915 

Prunum — Prune 917 

Frunus  Virginiana — Wild  Cherry 917 

Laurocerasus— Cherry  Laurel 917 

QuillajesB 918 

Quillaia— Soap  Bark 918 

Bubete 919 

Eubus— Blackberry 919 

Bubus  Idseus — Baspberry 919 

Boseae 920 

Oil  of  Bose 920 

Bosa  Centifolia — Cabbage  Bose— Pale  Bose 920 

Bosa  Gallica— Bed  Bose 920 

Bosa  Canina — Dog  Bose 920 

Cusso— Brayera     .        .        .        .        .        .    - 921 

PomesB 921 

Cydonium — Quince 921 

Myrtaceee 922 

Caryophyllus — Cloves .    .  922 

Pimenta — Allspice 923 

Cheken 923 

Oleum  Myrti— Oil  of  Myrtle 924 

Oleum  Cajuputi — Oil  of  Cajuput 924 

Eucalyptus — Oil  of  Eucalyptus 925 

Granatum — Pomegranate 926 

Papayaceae 927 

Papayotin — Papain - 927 

Cucurbltacese 927 

Colocynth 927 


xliv  CONTENT'S. 

PAGB 

Eoballium — JUlaterium •        •  928 

Pepo — Pumpkin 930 

Bryonia — Bryony 930 

Vmbelliferae 930 

Campylospermje 930 

Conium ...  931 

Orthospermae 932 

Asafcetida^Asafetida 932 

Galbanum 933 

Ammoniacum        . 933 

Eoeniculum — Fennel 934 

Anisum — Anise 935 

Anethum— DUl 936 

Carum — Caraway 936 

Sumbul 937 

Ccelospermse 937 

Coriander 937 

Cornaceee          .        .        .        .    > 938 

Cornusrr-Dogwood    .        . 938 


CHAPTEE  XXXIV. 

Phanerogams  (continued). 

Class  II.,  Dicotsledones  G-amofetal.s  (ConojjjrhORm),  pp.  939-1008. 

Caprifoliacese 939 

Sambucus 939 

Viburnum 939 

Rubiaceee  (Cinchonaoese) 939 

Cinohonese ,  939 

Cinchona  Flava — Yellow  Cinchona 940 

„        Bubra — Bed  „ 940 

Quinine  and  its  Salts 942 

Cinchonine 943 

Ixorese  (Coffere) 948 

Ipecacuanha      .        .        . 948 

Caffea — Coffee 950 

Catechu  (Pale) _ 951 

Valerianaceae 951 

Valerian 951 

Composites „ 952 

Pyrethrum        . 952 

Absinthium — Wormwood 953 

Tanacetum — Tansy 953 

Santonica — Santonin 954. 

Anthemis — Chamomile 955 

Matricaria — German  Chamomile 956 

Eupatorium — Thoroughwort 955 

Taraxacum — Dandelion ggg 

Lactuca — Lettuce 957 

Arnica 957 

Calendula — Marygold 959 


CONTENTS,  xlv 


PAGE 


Grindelia                                , 959 

Inula — Elecampane          ......        .  ■     ,        .  959 

Lappa-^Burdock 960 

Campanulaceae  (Lobeliacea) 960 

Lobelia ,        .    .  960 

Ericaceae 961 

Uva  TJrsi — Bearberry    ...........  961 

Chimaphila — Pipsissewa 962 

Oleum  Gualtherise — 9il  of  Wintergreen        .                962 

Sapotaceae     .                           963 

Gutta-percha 963 

Styraeaceae  . 963 

Benzoin — Benzoic  Acid 963 

OleacesB         ...... 965 

Olive  Oil 965 

Hard  Soap 966 

Soft  Soap     .        .        .      „v       .        •        ■     ; 966 

Glycerin 966 

Manna - 968 

Apocynaceee         . ,  968 

Apocynum — Canadian  Hemp 968 

Quebracho 969 

Asclepladaceee 970 

AsclepiaB — Pleurisy  Boot 970 

Asclepias  Incarnata — White  Indian  Hemp 970 

Hemidesmus 970 

Condurango 970 

Xoganiaceae 971 

Nux  Vomica 971 

Ignatia 971 

Strychnine 972 

Curare- , 976 

Gelsemium 977 

Spigelia — Pinkroot — Maryland  Pink 978 

Gentlanaceae 979 

Gentian .        .        .  979 

Chiretta 979 

Convolvulaceae 980 

Scammony 980 

Jalap 982 

Solanaceae .    .  983 

Dulcamara 983 

Capsicum 984 

Atropeae  • 984 

Belladonna — Atropine 984 

Hyoscyamus 990 

Stramonium 991 

Tobacco ,      .        .        .        .992 

Scrophulariaceae 994 

Digitalis   .  • 994 

Leptandra 1001 

Pedalineae 1002 

-Oleum  Sesami — Benne  oil    .        .        .        .        .        .        .       .,        .    .  1002 


xlvi  CONTENTS^ 

PASS 

Verbenaeeee  . 1002 

Lippia  Mexicana »    •  1002 

Lablatee        »»...... 1002 

Rosemary      >         » 1002 

Lavender .        > 1003 

Peppermint — Menthol. 1004 

Spearmint         »•.........••  1005 

•Thymol 1005 

Hedeoma — Pennyroyal 1006 

Marrubium — Horehound 1007 

Melissa— Balm «        •  1007 

Origanum — Wild  Marjoram         .........  1007 

Salvia— Sage    .  »  1008 

Scutellaria— Skull-cap 1008 


CHAPTEB  XXXV. 

Phanekogajde  (continued). 
Class  III.,  Dicotyledones  Monoohlamydej3  (Apeial2e),  pp.  1009-1035. 

Cnenopodlaceae 1009 

Chenopodium— Amerioan  Wormseed >  1009 

Oleum  Chenopodii 1009 

Pbytolaccaoeae 1009 

Phytolacca— Poke  berry 1009 

Polygonaceae 1010 

Eheum— Ehubarb 1010 

Eumex— Yellow  Dock 1011 

Arlstolochiaceee 1012 

Serpentary 1812 

Asarabacca 1012 

Piperaceae 1012 

Pepper— Piperine 1012 

Cubebs          .                 1013 

Matico 1014 

Myristlcacese 1015 

Myristica — Nutmeg 1015 

Macis — Mace 1016 

Xiaurlnese 1016 

Cinnamon 1016 

Goto 1017 

Parocoto 1017 

Camphor 1018 

Monobromated  Camphor      .        .        , 1019 

Sassafras 1020 

Nectandra— Bebeeru .        .  1021 

Santalacese iQ'21 

Oleum  Santali ,    .  102I 

Tbymelaceee 1022 

Mezereon 1022 

Euphorbiaceee 1022 

Cascarilla     ...  - .        .        .        ,  1022 


GOftttEKt&'  xltii 

PAGK 

Stillingia  .        .  ■     .        .        .        . 1022 

Croton  Oil -     .        .        .        .    .  1023 

Castor  Oil         .        . .  1024 

Kamala         .        . <  1025 

Vrtlcaceee 1025 

Ulmeee 1025 

TJlmua  , 1025 

Cannabineffi . ,         .         ,         .    ,  1026 

■    Cannabis  Indica — Indian  Hemp        .        .        .        ...        .        .  1026 

i    Cannabis  Americana — American  Cannabis   .        .        .        .        ,    .1026 

Hamulus — Lupulus — Hop 1027 

Mores , 1028 

Morus-^Mulberry 1028 

Artocarpeie   ...        .        .        . 1028 

Kcus— .Fig »        .  1028 

Juglandaceae    .„.„.„...  , .1029 

Juglans — Butternut 1029 

Hqmamelaceae 1029 

Hamamelis 1029 

Balsamiflorae  .         .         .■<*;.         *      ,■•         •         •         •         •    •  1030 

Styrax      .        .        .        .""'  .        /      .        '/      .  ...  1030 

Cupullferee        .........  ....  1030 

Querous— Oak  .        . 1030 

Galls    .        .        .        .        V 1031 

Tannic  Acid     .  1031 

Gallic  Acid  ' 1033 

Castanea — Chestnut .        .  1034 

Sallcaceee  .  .    .  1034 

Salix— Salioin 1034 


CHAPTEE  XXXVl. 

PniNEKOQAM^:  (continued). 

Glass  IV.,  Monocotyledones,  pp.  1036-1056. 

Orchldaceae 1036 

Vanilla 1036 

Cypripedium ,      .        .        ...        .        .  1036 

Scltamnaceee  (Zingiberaceas)   .        .        .  1036 

Zingiber — Ginger ,     .  .  .  1036 

Turmeric 1037 

Cardamoms 1038 

Zrldeae 1038 

Crocus— Saffron 1038 

Iris 1038 

Ullaceae 1039 

Allium— Garlic     . 1039 

Convallaria .        .  1040 

Squill 1049 

Aloe 1041 

Veratrum  Viride .    .  .1045 


xlviii  CONTENTS. 

PASS 

Cevadilla— Sabadjlla— rYeratrine .  .  .  ,  .  ...  .  •  •  1046 
Colehicum , 1049 

MUacese  (Smilaceso)     .   , , 1051 

Sarsaparilla 1051 

Palmacese    •        ......■        ...*-■  1052 

Areea 1052 

Aroldese 1052 

Calamus^Sweet  Flag - 1052 

Gramlneee ^ 1053 

Wheat— Flours-Bread— Starch 1053 

Conch  Grass 1054 

Pearl  Barley. 1054 

Malt 1054 

Sugar 1055 

Treacle 1055 

Oatmeal 1056 


CHAPTEE  XXXVH. 

Phaneboouix  (continued). 

Division  II.,  GraxospEiiKS,'  pp.  1057-1065. 

Conlferee ,    .  1057 

Terebinthina  Canadensis — Canada  Balsam 1057 

Thus  Americanum — Common  Frankincense 1057 

Turpentine 1057 

Oil  of  Turpentine .        .    .  1058 

Oil  of  Scotch  Fir "...  1059 

Terebene 1060 

Sanitas 1060 

Oleum  Succini — Oil  of  Amber 1060 

Besin        .        .        . 1061 

Larch  Bark 1061 

Burgundy  Pitch 1062 

Canada  Pitch 1062 

Tar 1062 

Oil  of  Tar ....  1063 

Thuja— Arbor  Vital 1063 

'  Juniper 1063 

Savin       » ....  1064 


CHAPTEE  XXXVIII. 

Sub-Kingdom  II.,  Cryptogams,  pp.  1066-1073. 

Fllices  . 1066 

Male  Fern 1066 

Mchenes 1067 

Cetraria — Iceland  Moss        .       .        .        . 1067 

Litmus     .       .        .  .        .        .........       ,        .  1067 


CONTENTS.  xlix 

PAGE 

rung*         .......                1067 

Muscarine        ............  1067 

Agaricus  Albus     . 1068 

ErgOt— Ergotin 1068 

TJstilago 1073 

Beer  Yeast 1073 

Aleas 1073 

Chondrus—  Irish  Moss 1073 


SECTION  VI. 

ANIMAL  KINGDOM. 

CHAPTER  XXXIX.,  pp.  1077-1099. 

Class  Mammalia 1077 

Order  Bodentia 1077 

Castor 1077 

Order  Buminantia 1077 

Musk 1077 

Suet 1078 

Lanolin .  1078 

Curd  Soap 1079 

Milk— Koumiss— Kephir 1079,  1080 

Milk  Sugar 1080 

Pepsin 1081 

Ox  Gall ...  1081 

Keratin 1083 

Order  Pachydermata 1084 

Lard 1084 

Order  Cetacese 1085 

Spermaceti 1085 

Class  Aves         .  - 1085 

Order  Gallinse 1085 

Egg-Albumen  and  Yolk 1085 

Class  Pisces 1086 

Order  Sturiones 1086 

Isinglass — Ichthyocolla 1086 

Order  Teleosteas— Family  Gadidse 1087 

Cod  Liver  Oil 1087 

Class  Inseeta 1089 

Order  Hymenoptera 1089 

Honey 1089 

Wax  ....  1089 

Order  Hemiptera 1090 

Coccus — Cochineal 1090 

Order  Coieoptera 1091 

Cantharis — Spanish  Flies 1091 

Class  Annelida 1095 

Hirudo — the  Leech 1095 

c 


CONTENTS. 


APPENDIX. 

PAO» 

Methylal 1097 

Urethane 1097 

Iodol 1099 

Strophanthus  hispidus— Strophanthin 1099 

Dead  Space 1100 

GENEEAL  INDEX 1103 

INDEX  OF  DISEASES  AND  BEMEDIES 1177 

BIBLIOGBAPHICAL.  INDEX    .       .       9       ......   .  1239 


ADDITIONS  MADE  IN  1890 
TO  THE  BRITISH  PHARMACOPOEIA  OP  1885. 

PAGE 

Acetanilidum  (Antifebrin)  (of.  p.  825) [1110] 

Acetnm  Ipecacuanb.se  (cf.  p.  949) [1114] 

Adeps  LansB  (Anhydrous  Lanolin)  (cf.  p.  1078) [1116] 

Adeps  Lanse  Hydrosus  (Lanoline) [1116] 

'  Antifebrin.'     See  Acetanilidum 

'  Antipyrine '  (p.  824).     See  Phenazonum 

'  Blaud's  Pill.'     See  Pilula  Ferri 

Emplastrum  Menthol  (cf.  p.  1004) [1116] 

Eucalypti  Gummi  (cf.  p.  925) [1116] 

Euonymi  Cortex  (cf.  p.  894) [HOG] 

'  Euonymin.'     See  Extractum  Euonymi  Siccum. 

Extractum  Euonymi  Siccum  (cf.  p.  403) [1106] 

Extractum  Hamamelidis  Liquidum  (cf.  p.  1029) [1108] 

Extractum  Hydrastis  Liquidum  (cf.  p.  839) [1107] 

'  Fehling's  Solution.'     See  Solution  of  Potassio-Cupric  Tartrate 

Gelatinum  (cf.  p.  1086) [1106] 

Glonoine,  Solution  of.     See  Liquor  Trinitrini 

Glusidum  (cf.  Saccharin,  p.  825) [1112] 

Hamamelidis  Cortex [1108] 

Hamamelidis  Folia  (cf.  p.  1029) [1108] 

Homatropinae  Hydrobromas  (cf.  p.  219) [1114] 

'  Huile  de  Cade.'     See  Oleum  Cadinum 

Hydrastis  Ehizoma  (cf.  p.  839) [1107] 

'  Lanoline.'     See  Adeps  Lanse  Hydrosus 

Liquor  Cocainte  Hydrochloratis  (cf.  p.  877) [1113] 

Liquor  Morphinffl  Sulphatis  (cf.  p.  848) [1113] 

Liquor  Trinitrini  (cf.  p.  788) [1115] 

Magnesii  Sulphas  Effervescens  (cf.  p.  659) [1105] 

Mistura  Olei  Bicini [1105] 

Nitroglycerine,  Solution  of.     See  Liquor  Trinitrini 

Oleum  Cadinum [1117] 

Paraldehydum  (cf.  p.  778) [1113] 

Phenacetinum [1110] 

Phenazonum  (Antipyrine)  (cf.  p.  824) [1111] 

Picrotoxinum  (cf.  p.  842) [1114] 

Pilula  Ferri [1115] 

Pulvis  Sods  Tartaratse  Effervescens [1104] 

■  Saccharin.'    See  Glusidum 


lii 


CONTENTS. 


'  Seidlitz  Powder.'    See  Pulvis  Sodte  Tartaratas  Effervescens 

Sodii  Benzoas  (of.  pp.  78  and  964) 

Sodii  Nitris  (cf.  pp.  331  and  788)     . 

Sodii  Phosphas  Effervescens  (of.  pp.  626  and  403) 

Sodii  Sulphas  Effervescens  (cf.  pp.  625  and  403 

Solution  of  Potassio-Cupric  Tartrate 

Stramonii  Folia  (cf.  p.  991)     . 

Strophantus  (cf.  p.  1099)  . 

Sulphonal 

Suppositoria  Glycerini         . 
Syrupus  Ferri  Subchloridi 
Tinctura  Hamamelidis 
Tinctura  Hydrastis  (cf.  p.  403) 
Tinctura  Strophanthi  (cf.  p.  1099) 
Trochisci  Sulphuris  (cf .  p.  547) 
Unguentum  Conii  (cf.  p.  932) 
Unguentum  Hamamelidis  (cf.  p.  1029) 


[1109] 
[1115] 
[1105] 
[1105] 
[1117] 
[1114] 
[1115] 
[1113] 
[1106] 
[1116] 
[1108] 
[1107] 
[1115] 
[1104] 
[1108] 
[1108] 


MATERIA  MEDICA  AND  THERAPEUTICS. 


B 


INTRODUCTION. 


By  Materia  Medica  we  understand  a  knowledge  of  the 
remedies  employed  in  medicine.  This  knowledge  may  be  sub- 
divided into  several  divisions :  Materia  Medica  proper,  Pharmacy, 
Pharmacology,  and  Therapeutics. 

By  Materia  Medica  proper  we  mean  an  acquaintance  with 
the  remedies  used  in  medicine,  the  places  whence  they  come,  the 
crude  substances,  plants  or  animals  which  yield  them,  the  methods 
by  which  they  are  obtained,  and  the  means  of  distinguishing  their 
goodness  or  purity,  or  of  detecting  fraudulent  adulteration. 

By  Pharmacy  we  mean  the  methods  by  which  drugs  are 
prepared  and  combined  for  administration. 

By  Pharmacology  we  mean  a  knowledge  of  the  mode  of 
action  of  drugs  upon  the  body  generally,  and  upon  its  various 
parts.  It  is  of  comparatively  recent  growth,  but  is  now  one  of  the 
most  important  subdivisions  of  Materia  Medica. 

By  Therapeutics  we  understand  a  knowledge  of  the  uses 
of  medicines  in  disease. 

Therapeutics  may  be  either  etnpirical  or  rational.  By  em- 
pirical we  mean  that  drugs  are  tried  haphazard,  or  with  little 
knowledge  of  their  action  in  some  cases,  and,  being  found  success- 
ful, are  again  administered  in  other  cases  which  seem  to  be  similar. 

Perhaps  the  best  example  of  the  empirical  use  of  a  remedy  is 
that  of  quinine  in  ague.  We  do  not  know  with  certainty  what 
the  pathological  conditions  are  in  this  disease,  nor  how  quinine 
acts  upon  them  ;  all  we  know  is  that  it  has  proved  useful  in  cases 
of  ague  before,  and  therefore  we  give  it  again. 

Rational  therapeutics  consists  in  the  administration  of  a 
drug  because  we  know  the  pathological  conditions  occurring  in 
the  disease,  and  know  also  that  the  pharmacological  action  of 
the  drug  is  such  as  to  render  it  probable  that  it  will  remove  or 
counteract  these  conditions. 

Bational  therapeutics  is  the  highest  branch  of  medicine.  Its 
advance  is  necessarily  slow,  because  it  is  based  upon  pathology 
on  the  one  hand  and  pharmacology  on  the  other,  and  both 
of  these  rest  upon  physiology,  which  in  its  turn  rests  upon 
physics  and  chemistry.     It  is  only  with  the  development  of  the 

B  2 


4  INTRODUCTION. 

fundamental  sciences  that  those  which  rest  upon  them  can  grow ; 
and  when  we  consider  that  chemistry  as  a  science  is  not  much 
more  than  a  hundred  years  old,  and  when  we  see  the  advances 
it  has  already  made,  we  cannot  but  be  hopeful  for  the  future  of 
therapeutics. 

occasionally  we  hear  the  question  asked,  '  What  is  the  use  of 
knowing  the  action  of  all  sorts  of  drugs  upon  the  different  parts 
of  the  animal  body,  and  what  is  the  use  of  knowing  the  altera- 
tions in  the  muscles,  vessels,  or  nerves  which  occur  under  patho- 
logical conditions,  seeing  that  in  many  instances  such  a  know- 
ledge cannot  be  utilised  for  the  treatment  of  disease  ? '  As  well 
might  we  ask,  on  seeing  a  half-built  bridge,  '  What  is  the  use  of 
laying  the  foundations  and  building  the  piers,  seeing  -no  one  can 
walk  across  from  one  end  to  the  other  ?•' 

As  an  example  of  rational  therapeutics,  we  may  take  the  use 
of  nitrite  of  amyl  in  certain  forms  of  angina  pectoris.  The 
obvious  symptoms  in  this  disease  are  intense  pain  in  the  region 
of  the  heart,  and  fear  of  impending  death.  Sphygmographic 
tracings  of  .the  pulse  taken  during  this  condition  show  that  the 
tension  within  the  heart  and  vessels  begins  to  increase  as  the 
pain  comes  on,  and  reaches  such  a  height  that  the  heart  can 
barely  empty  itself.  Observations  on  animals  have  shown  that 
nitrite  of  amyl  lessens  the  tension  of  the  blood  in  the  vessels  ; 
and  we  therefore  give  it  in  angina  pectoris  with  the  expectation 
that  it  will  dimmish  the  tension  and  remove  the  pain,  and  we  find 
that  it  succeeds. 

But  this  example  shows  us  only  the  first  stage  of  rational 
therapeutics.  We  have  removed  by  a  remedy  the  pathological  con- 
dition which  immediately  gives  rise  to  the  pain  and  danger  of  the 
patient,  but  the  antecedent  alterations  of  the  heart,  bloodvessels,' 
and  nervous  system,  which  led  to  the  occurrence  of  the  pain,  are 
unaltered  by  the  remedy.  In  order  that  our  therapeutics  should 
be  completely  successful,  we  must  seek  still  further  for  something 
which  will  restore  the  circulation  and  nervous  system  to  its 
normal  condition  and  bring  the  patient  back  to  a  state  of  perfect 
health. 

Sometimes  we  are  able  to  do  this.  For  example,  we  oc- 
casionally meet  with  a  kind  of  pain  in  the  cardiac  region  which 
closely  resembles  angina  pectoris,  and  is  probably  a  form  of 
it.  Acting  on  the  general  principle  that  pain  is  due  to  irritation 
somewhere,  though  not  necessarily  at  the  place  where  the  pain 
is  felt,  we  seek  for  the  irritant.  We  find  swelling  and  tenderness 
over  the  sternum  at  the  junction  of  the  manubrium  and  the 
body,  and  we  look  upon  this  as  the  irritant  which  is  exciting 
the  cardiac  pains.  Judging  this  swelling  to  be  syphilitic, 
we  give  iodide  of  potassium ;  the  swelling  subsides,  and  the 
angina-like  pain  completely  disappears. 

But  sometimes  it  is  impossible  to  remove  the  cause  of  the 


INTRODUCTION.  5 

disease,  and  all  that  we  can  do  is  to  alleviate  symptoms. 
The  organic  changes  which  have  occurred  in  the  course  of  the 
disease  may  be  so  great  that  we  can  hardly  hope  that  any  remedy 
will  ever  be  discovered  sufficiently  powerful  to  remove  them.  We 
must  therefore  try  to  prevent  them. 

Preventive  medicine,  or  prophylaxis,  is  daily  becoming 
more  important,  and,  possibly  before  the  end  of  this  century, 
medical  men  will  be  employed  more  to  prevent  people  from 
becoming  ill  than  to  cure  them  when  disease  has  become  fairly 
established. 

This  may  at  least  be  the  case  in  regard  to  the  contagious  and 
infectious  diseases,  which  attack  people  as  it  were  by  accident, 
and  are  totally  unconnected  with  their  ordinary  work  or  pleasure. 
It  is  too  much  to  hope  that  other  diseases  which  depend  upon 
hereditary  tendencies,  overwork,  or  over-indulgence,  will  disappear., 
for  there  can  be  little  doubt  that  men  in  the  future  will,  as  in  the 
past,  knowingly  sacrifice,  not  only  their  health,  but  their  life,  to 
ambition,  duty,  or  pleasure. 

The  advance  of  this  branch  of  medicine  has  been  greatly 
aided  by  the  recent  increase  in  our  knowledge  of  the  life-history 
of  microbes  and  their  action  in  causing  disease.  Our  power  to 
prevent  disease  will  become  greater  when  we  know  accurately 
the  action  of  various  drugs  in  destroying  these  microbes  or 
preventing  their  growth. 

Pharmacology  has  made  such  rapid  advances  of  late  years 
that  it  is  exceedingly  difficult  for  many  men  who  are  engaged  in 
practice  to  understand  thoroughly  either  the  methods  by  which 
it  is  studied,  or  its  results.  Many  students  also,  although  they 
may  be  able  to  pass  a  good  examination  in  physiology,  find  it 
difficult  to  apply  their  physiological  knowledge  to  pharmacology ; 
and  therefore  in  discussing  the  action  of  drugs  upon  the  various 
functions  of  the  body,  I  have  sometimes  entered  more  fully  into 
the  physiology  of  those  functions  than  may  seem  to  some  at  all 
either  necessary  or  advisable. 

In  discussing  pharmacological  questions,  we  are  accustomed 
to  speak  of  the  action  of  a  drug  on  the  body  or  on  its  various 
parts ;  but  we  must  remember  the  effect  produced  is  not  due 
to  a  one-sided  action — that  what  we  actually  mean  is  the 
re-action  between  the  drug  and  the  various  parts  of  the  body. 

In  some  instances  we  know  that  the  drug  itself  is  changed  in 
the  body,  as  well  as  the  function  of  the  body  modified  by  the 
drug ;  and  even  in  those  cases  where  the  drug  itself  is  eliminated 
from  the  body  apparently  unaltered,  it  is  probable  that  it  has 
entered  into  various  chemical  combinations  within  the  body 
while  circulating  in  the  blood  or  present  in  the  tissues. 


SECTION  I. 

GENERAL  PHARMACOLOGY  AND 
THERAPEUTICS. 


OHAPTEE  I. 

GENEEAL  EELATIONS  BETWEEN  THE  OEGANISM  AND 
SUBSTANCES  AFFECTING  IT. 


In  discussing  the  inter-action  between  the  animal  organism  and 
the  substances  which  act  upon  it,  it  may  be  well  to  take  a  slight 
glance  first  at  the  substances  which  compose  its  environment, 
although  these  will  be  afterwards  considered  more  in  detail. 

Of  the  elements  composing  the  earth  on  which  we  live  we 
at  present  know  about  seventy-two  whose  existence  appears  well- 
established.  They  are  given  in  the  accompanying  table.  The 
atomic  weights  assigned  to  them  cannot  be  regarded  as  absolutely 
correct.  There  are  sometimes  considerable  discrepancies  between 
those  given  by  different  authorities,  and  those  which  are  accepted 
to-day  may  require  to  be  altered  again  in  accordance  with  the 
more  exact  knowledge  which  future  observations  may  supply. 
There  are  slight  differences  between  several  of  them  as  given  in 
the  British  and  United  States  Pharmacopoeias. 


TABLE  OF  ELEMENTS. 

Element 

Symbol 

Valency  or 
Atomicity 

Atomic 

Weight, 

B.P. 

Atomio 
Weight, 

r.s.  P. 

Atomic  Weight 

very  accurately 

determined ' 

♦Aluminium         • 

Al.       . 

II.  &  IV. 

27-0 

27-0 

27-009 

♦Antimony         \ 
(Stibium)/ 

*  Arsenicum . 

Sb. 

in.  &  v. 

120-0 

120-0 

119-555 

As. 

III.  &  V. 

75;0 

74-9 

74-918 

•Barium 

Ba.       . 

ii. 

137-0 

136-8 

136-763 

Beryllium  or    "1 
Glueinumj 

Be  or  G . 

ii. 

9-0 

9-0 

9-085 

♦Bismuth     . 

Bi. 

UI.&V. 

209-0 

210-0 

207-523 

*Boron 

. 

B  . 

— 

11-0 

11-0 

10-941 

'  *Bramme 

. 

Br 

i. 

80-0 

79-8 

79-768 

Cadmium 

. 

Cd 

ii. 

111-8 

111-8 

111-835 

Caesium 

, 

Cs. 

i. 

133-0 

132-6 

132-583 

♦Calcium 

. 

Ca 

n. 

40-0 

40-0 

39-99 

*Cwrbon 

• 

C  . 

n.  &  iv. 

120 

120 

11-9736 

♦Cerium 

, 

Ce. 

IV. 

141-0 

141-0 

140-424 

*Chlorme 

, 

CI. 

i. 

35-5 

35-4 

35-37 

♦Chromium 

. 

Cr. 

n.  &  iv. 

52-S 

52-4 

52-009 

Cobalt 

• 

Co. 

n.  &  iv. 

58-9 

58-9 

58-887 

Those  marked  with  ♦  are  contained,  either  simply  or  in  combination,  in  the 
British  Pharmacopoeia.  Those  printed  in  italics  are  non-metallic  elements.  Their 
atomio  weights  are  given  as  in  the  B.  P. 

1  From  Ira  Bemsen's  Principles  of  Theoretical  Chemistry. 


10  PHABMACOLOGY  AND   THEEAPEUTICS.     [sect.  i. 

TABLE  OF  ELEMENTS— continued. 


Valency  or 
Atomicity 

Atomic 

Atomic 

Atomic  Weight 

Element 

Symbol 

Weight, 
B.P. 

Weight, 
U.S.  V. 

very  accurately 
determined 

Columbium  vide 

Niobium 

"Copper  (Cuprum) 

Cu. 

II. 

63-4 

63-2 

63-173 

Didymium  . 

Di. 

rv. 

145-4 

144-6 

145-4 

Erbium 

ErorEb1 
orE 

F  . 

— 

166-0 

165-9 

165-891 

Fluorine     . 

i. 

19-0 

19-0 

18-984 

Gallium 

Ga 

IV. 

70-0 

68-8 

69-9 

♦Gold  (Aurum)     . 

Au 

i.  &  in. 

196-5 

196-2 

196-155 

Glueinum      vide 

Beryllium 

Holmium    . 

.               . 



— 





*Hydrogen   . 

B  . 

i. 

1-0 

1-0 

1-0 

Indium 

In. 

i.  &  in. 

113-4 

113-4 

113-398 

*Iodime 

I   . 

i. 

127-0 

126-6 

126-557 

Iridium 

Ir  . 

II.  &  IV. 

192-7 

192-7 

192-651 

♦Iron  (Ferrum)     . 

Fe. 

II.  &  IV. 

56-0 

55-9 

55-913      ■ 

Lanthanum 

La. 

IV. 

139-0 

138-5 

138-526 

*Lead  (Plumbum) 

Pb. 

II.  &  IV. 

207-0 

206-5 

206-471      ' 

*Lithium 

Li. 

I. 

7-0 

7-0 

7-0073    ■ 

♦Magnesium 

Mg 

II. 

24-0 

24-0 

23-959 

*Manganese 

Mn 

II.  &  IV. 

55-0 

54-0 

53-906 

^Mercury           \ 
(Hydrargyrum)  / 

Hg 

II. 

200-0 

199-7 

199-712 

Molybdenum 

Mo 

95-5 

95-5 

95-527 

Nickel 

Ni. 

II.  &  IV. 

58-0 

58-0 

57-928      i 

Niobium  or       "1 
Columbium/ 

Nb 

V. 

94-0 

94-0 

*Nitrogen     . 

N  . 

III.  &  V. 

14-0 

14-0 

14-021 

Osmium 

Os. 

II.  &  IV. 

198-5 

198-5 

198-494 

*  Oxygen 

0  . 

II. 

16-0 

16-0 

15-9633 

Palladium  . 

Pd. 

II.  &  IV. 

105-7 

105-7 

105-737 

*Phosphorus 

P  . 

III.  &  V. 

31-0 

31-0 

30-958 

♦Platinum    . 

Pt. 

II.  &  IV. 

195-0 

194-4 

194-415 

♦Potassium        1 
(Ealium)  / 

K  . 

I. 

39-0 

39-0 

39-019 

Bhodium    . 

Eh 

H.  &  IV. 

104-0 

104-1 

104-055 

Bubidium  . 

Bb 

I. 

85-3 

85-3     ' 

85-251 

Buthenium 

Eu 

II.  &  IV. 

104-2 

104-2 

104-217 

Samarium  . 

Sm 

— 

150-0 

150-021 

Scandium  . 

Sc. 

— 

44-0 

44-0     ' 

43-98 

Selenium    . 

Se. 

II. 

78-8 

78-8 

78-797 

Silicon 

Si. 

IV. 

28-0 

28-0 

28-195 

♦Silver  (Argentum) 

Ag.        . 

I.  (?  II.) 

108-0 

107-7 

107-7 

♦Sodium(Natrium) 

Na 

I. 

23-0 

230 

22-998 

Strontium  . 

Sr. 

II. 

87-4 

87-4 

87-374 

*Sulphur     . 

S  . 

II. 

32-0 

32-0 

31-984 

Tantalum  . 

Ta. 

III.  &  V.  ' 

182-0 

182-0 

182-144 

Tell/wrium  . 
Terbium     . 

Te. 

n. 

128-0 

128-0 

127-96 

Thallium    . 

Tl  or  Th' 

III. 

203-7 

203-7 

203-715 

Thorium     . 

Th 

IV. 

233-0 

233-0 

233-414 

Thulium     . 

• 

—          1 

— 

1  Er,  Boscoe  and  Schorlemmer,  Treatise  on  Chemistry,  vol   i   p    54     Eb 
PbWneB,  edited  by  Watts,  12th  ed.  vol.  i.  p.  401.    E,  Ira  Bemsen's  Principles  of 
Theoretical  Chemistry. 


CHAP.  I.] 


GENEEAL  EELATIONS. 


11 


TABLE   OF  ELEMENTS— continued. 

Element 

Symbol 

Valency  or 
Atomicity 

Atomic 

Weight, 

B.P. 

Atomic 
Weight, 
U.S.  P. 

Atomic  Weight 

very  accurately 

determined 

*Tin  (Stannum)   . 
Titanium    . 
Tungsten    ■ 
Uranium    . 
Vanadium  .        . 
Ytterbium  . 
Yttrium      , 
*Zinc          .        . 
Zirconium .        . 

Sn. 
Ti. 
W. 
U  . 
V  . 
Yb. 

y  . 

Zn 
Zr. 

II.  &  IV. 
IV. 
VI. 

IV.  &  VI. 

III.  &  V. 

IV. 

II. 

IV. 

118-0 
49-8 

184-0 

240-0 
51-3 

172-8 
89-8 
65-0 
90-0 

117-7 
48-0 

183-6 

238-5 
51-3 

172-7 
89-8 
64-9 
90-0 

117-698 
49-846 

183-61 

239-8 
51-256 

172-761 
89-816 
64-9045 
89-367 

Nature  of  the  Elements. 

Considerable  additions  have  been  made  to  the  number  of  elements  during 
late  years.  The  reason  of  this  is  that  the  spectroscope  has  indicated  the 
presence  of  metals  previously  unknown,  and  by  the  use  of  proper  means  they 
have  been  obtained  in  a  separate  condition.  These  substances  are  termed 
elements  because  we  do  not  at  present  know  how  to  split  them  up  in  such  a 
manner  as  to  prove  that  they  are  compounds.  But  it  is  not  improbable  that 
they  are  compounds,  just  as  we  now  know  that  potash  and  soda  are  com- 
pounds ;  although  before  Sir  Humphry  Davy  split  them  up  into  oxygen  and 
a  metal  they  were  supposed  to  be  elements.  Indeed,  recently  much  evidence 
has  been  brought  to  show  that  the  substances  which  we  call  elements  are 
really  compounds. 

It  is  from  an  examination  of  the  spectroscopic  character  of  the  elements 
at  different  degrees  of  temperature  that  Lockyer  has  been  able  to  obtain 
sufficient  data  to  justify  the  definite  formulation  of  the  hypothesis  that 
all  the  elements  we  know  are  really  compounds,  or,  to  speak  perhaps  more 
precisely,  are  really  different  forms  of  aggregation  of  one  kind  of  matter.1 
According  to  this  hypothesis  the  matter  of  which  the  universe  is  composed 
was  at  one  time  equally  distributed  through  space,  and  uniform  in  kind. 
The  atoms  then  coalesced  in  various  groups  of  two,  three,  or  more;  and 
these,  again  grouping  themselves  together  still  further,  formed  aggregates  of 
more  and  more  complex  composition.  These  aggregates  are,  it  is  supposed, 
the  elements  with  which  we  are  acquainted.  Most  of  those  complex  mole- 
cules are  perfectly  stable  at  ordinary  temperatures ;  and  so  their  composition 
remains  constant  under  the  conditions  usual  at  the  surface  of  this  earth. 

But  when  they  are  subjected  to  increased  temperatures  in  the  laboratory, 
rising  from  that  of  the  Bunsen  lamp  to  the  electric  arc,  and  then  to  the 
electric  spark  or  to  still  higher  temperatures  in  the  sun,  their  spectroscopic 
appearances  give  evidence  of  decomposition  into  simpler  molecules.  When 
the  elements  are  subjected  to  cold  and  pressure  the  molecules  which  compose 
them  come  closer  together,  and  we  get  them  forming  a  solid  substance.  Heat 
tends,  by  communicating  vibrations  to  them,  to  shake  the  molecules  further 
apart,  and  to  produce  a  liquid  condition.  Still'  greater  heat  shakes  the 
molecules  further  apart  still,  and  produces  a  gaseous  condition. 

In  all  those  conditions  the  molecules  of  the  element  become  more  complex 
by  reduction  of  temperature  or  increase  of  pressure,  and  simpler  by  increase 
in  temperature  or  reduction  in  pressure.2  Exceedingly*  great  heat  or  elec- 
tricity appears  to  shake  apart  still  further  the  constituents  of  the  element,  so 
as  to  resolve  it  into  simpler  combinations  of  the  elementary  substance  of 
which,  according  to  the  hypothesis,  it  is  composed. 

This  shaking  apart  of  the  component  elements  is  known  to  exist  in  com- 

1  Lockyer,  Phil.  Trans.  1874,  p.  492  et  seq. 

2  According  to  another  hypothesis,  bodies  are  supposed  to  have  molecules  of  one 
degree  of  complexity,  and  the  difference  between  solid,  liquid,  and  gaseous  bodies  is 


12 


PHAKMACOLOGY  AND  THEBAPEUTTCS.     [sect.  i. 


pounds,  and  to  it  the  name-  of  dissociation  has  been  given.  Thus  when 
chalk  or  limestone  is  exposed  to  the  action  of  heat  it  becomes  dissociated 
into  carbonic  acid  and  lime,  CaCOs  =  CaO  +  C02.  This  process  is  readily  re- 
versible by  reversing  the  conditions.  Thus  the  Erne  and  carbonic  acid  which 
are  dissociated  by  heat  readily  recombine  in  the  cold  CaO  +  C04  =  CaCOs. 

When  matter  is  solid  the  molecules  of  which  it  is  composed  are  sup- 
posed to  be  large  and  close  together.  When  in  the  state  of  vapour  or  gas, 
these  molecules  are  smaller  and  much  further  apart. 

Solid,  liquid,  or  densely  gaseous  matter,  when  its  molecules  are  agitated 
by  heat,  gives  a  continuous  spectrum.  Gaseous  and  vaporous  matters,  when 
their  molecules  are  agitated  at  lower  pressures  or  higher  temperatures  by 
heat  or  electricity,  give  a  discontinuous  spectrum  consisting  of  bands  or  lines. 

Between  those  extremes  we  have,  as  a  rule,  three  other  intermediate 
kinds  of  spectra :  first,  a  continuous  spectrum  in  the  red ;  next,  a  continuous 
spectrum  in  the  blue ;  next,  a  fluted  spectrum,  and  after  thatthe  line  spectrum 
already  mentioned. 

In  all  those  kinds  of  spectrum,  however,  we  are  supposing  that  the  ele- 
mentary molecules  are  still'  intact ;  they  are  only  more  or  less  separated. 

Compound  bodies,  like  simple  bodies,  give  definite  spectra.  The 
spectrum  of  a  simple  metal  consists  of  lines  which  increase  in  number  and 
thickness  as  the  pressure  of  the  vapour  or  its  quantity  in  a  given  space  is 
increased.  The  spectrum  of  a  compound  body  consists  chiefly  of  channelled 
spaces  and  bands  which  increase  in  the  same  manner.  The  greater  the  number 
of  molecules  in  a  cubic  inch  or  cubic  millimetre,  and  the  more  violently  they 
are  agitated,  the  more  complex  is  the  spectrum  until  it  becomes  continuous. 

The  smaller  the  number  of  molecules  in  a  given  space,  the  more  simple  is 
the  spectrum,  which  then  consists  of  a  few  lines  only. 

When  a  compound  is  exposed  to  heat,  so  as  to  dissociate  it  into  its  com- 
ponent parts  the  spectroscopic  bands  characteristic  of  the  compound  become 
thinner,  and  the  lines  of  the  metal  increase  in  number,  as  shown  in  the 
accompanying  diagram  where  the  bands  exhibited  by  calcium  chloride  in  the 
flame  of  a  Bunsen's  burner,  disappear,  and  are  replaced  by  lines  only,  when 


4      - 

11 

'  III  III 

Fia.  1.— Spectrum  of  calcium  chloride.  (1)  In  the  flame  of  a  Bunsen's  burner,  showing  the 
channelled  spaces  and  bands  of  a  oompound.  (2)  In  an  electric  spark,  showing  the  lines  of 
the  element  calcium.    (After  Roscoe.) 

an  electric  spark  is  used.  When  an  element  is  treated  with  more  and  more 
heat  and  electricity  it  likewise  gives  exactly  the  same  kind  of  evidence  of 
dissociation— bands  disappearing,  and  lines  becoming  thinner.  Besides  this, 
new  lines  make  their  appearance  with  every  large  increase  of  temperature. 

This  behaviour  of  the  element  appears  to  show  that  it  also  is  a  compound, 
but  that  it  is  stable  under  ordinary  conditions,  and  is  only  dissociated  at  a 
high  temperature. 

,  Other  proofs  of  this  hypothesis  are  derived  from  a  comparison  of  the  spectra 
of  the  elements  as  observed  in  our  laboratories  with  their  spectra  in  the  sun. 

A  comparison  «of  the  two  hypotheses  shows  us  that  as  on  the  old 
hypothesis  each  element  represents  a  specjes  and  is  unvariable,  its  spec- 
trum ought  to  be  always  the  same  in  our  laboratories  and  in  the  sun :  and 
the  same  in  sun-spots  as  in  prominences,  and  the  same  at  all  periods  of  the 
sun's  activity. 

supposed  to  depend  on  the  difference  in  the  free  path  of  the  molecule.  But  accord- 
ing to  the  new  view,  the  difference  in  the  complexity  of  the  molecule  itself  is  sufficient 
to  explain  the  phenomena. 


qhat.  i.]  GENEEAL  RELATIONS.  13' 

Under  the  new  hypothesis  the  spectra  off  metals  in  our  laboratories  and 
in  the  sun  should  not  resemble  each  other ;  they  should  be  different  in  sun- 
spots  and  in  prominences,  because  the  spot  is  cooler  than  the' prominence; 
and  they  should  vary  at  the  time  of  the  sun's  activity  because  the  sun  is 
hotter  at  the  maximum  of  the  sun-spot  period,  and  therefore  there  should  be 
a  greater  amount  of  dissociation  amongst  the  elements  at  that  period. 

As  a  matter  of  fact  we  find  that  the  spectra  in  our  laboratories  and  in  the 
sun  do  not  resemble  each  other  (Fig.  2) ;   that  those  of  the  same  element 


m 


B 


FEEBLE  SPARK 


Fig.  2. — Diagram  of  the  spectrum  of  lithium  under  various  conditions  of  temperature. 
(After  Lockjer,  Boy.  Sac.  Proa.  Deo.  12, 1878.) 

m  the  sun-spot  and  prominences  are  as  dissimilar  as  of  any  two  elements ; 
and  that  the  spectra  of  the  elements  in  the  sun  do  vary  with  the  maximum ? 
of  the  sun-spot  period. 

On  the  old  hypothesis  the  spectra  of  prominences  should  also  consist  of 
lines  familiar  to  us  in  our  laboratories,  because  solar  and  terrestrial  elements 
are  the.  same,  while,  according  to  the  new  hypothesis,  the  spectra  of  promi- 
nences should  be  unfamiliar,  because  the  prominences  represent  outpourings 
from  a  body  hot  enough  to  prevent  the  atoms  of  which  our  elements  are 
composed  from  coming  together. 

As  a  matter  of  fact,  the  lines  in  the  prominences,  with  the  exception  of 
those  of  hydrogen,  magnesium,  calcium,  and  sodium,  are  either  of  unknown 
origin,  or  are  feeble  lines  in  the  spectra  of  known  elements.  Spectroscopic 
observation,  therefore,  leads  to  the  belief  that  the  so-called  elements  are 
really  compounds,  the  component  parts  of  which  are  kept  apart  by  high 
temperatures  in  the  sun  and  stars,  but  unite  when  the  temperature  decreases. 

By  the  powerful  vibrations  imparted  to  them  by  the  electric  spark,  they 
may  be  dissociated  in  the  laboratory ;  but,  as  no  means  has  yet  been  devised 
of  separating  the  components,  they  again  unite  to  form  the  original  body, 
just  as  hydrogen  and  oxygen,  into  which  steam  is  dissociated  by  passing  it 
through  a  strongly  heated  tube,  almost  instantly  combine  again  to  form  water 
unless  they  are  separated  by  means  of  the  more  rapid  diffusion  of  hydrogen 
through  a  porous  tube. 

The  difficulty  in  accepting  this  evidence  lies  in  the  fact  that  we  have 
hitherto  been  unable  to  isolate  the  substances  into  which  the  elements  are 
supposed  to  be  dissociated:  as  these  after  their  dissociation  at  once  recombine 
and  again  form  the  original  substance. 

One  proof,  however,  that  the  supposed  components  of  the  element  calcium 
may  remain  permanently  separated,  is  afforded  by  the  fact  that  in  the 
spectra  of  two  stars,  Sirius  (Fig.  3)  and  a  Lyrse,  which  are  very  bright,  and 
probably  very  hot,  only  one  of  the  ultra-violet  lines  of  calcium  is  represented. 


1AFU 
FLfl 


Fig.  3. — Diagram  of  the  speotrum  of  calcium  under  various  conditions  of  temperature.    In  the 
spectrum  of  Sirius  the  line  K  is  absent,  while  it  is  very  strongly  marked  in  the  solar  spectrum. 

But  we  have  also  other  evidence  of  the  compound  nature  of  the  elements, 
which,  although  it  was  not  sufficient  of  itself  to  force  us  to  abandon  our  old 
ideas  of  their  simple  nature,  is  yet  strongly  corroborative  of  the  spectroscopic 
evidence.  Thus  we  find  that  oxygen  is  broken  up  by  electricity,  and  that 
the  atoms  of  which  its  molecules  are  composed,  rearrange  themselves 
so  as  to  form  what  is  to  all  intents  and  purposes  a  new  element,  ozone, 
having  a  much  closer  resemblance  to  chlorine  than  to  oxygen  in  its  activity, 


14 


PHARMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


although  its   compounds  with  metals  appear   to   be   identical   with   those 
of  oxygen.  • 


Fig.  4. — Diagram  to  Illustrate  the  formation  of  ozone  by  electricity,  a  represents  oxygen,  through 
which  a  spark  is  passing ;  &  after  it  has  passed.  The  double  rings  are  intended  to  represent 
molecules  of  oxygen,  each  containing  two  atom3.  As  the  electric  spark  passes  through  the 
oxygen  it  breads  up  the  first  molecule,  carrying  one  atom  on  to  join  the  second  molecule  of 
oxygen,  and  form  one  of  ozone.  The  atom  which  is  left  joins  another  molecule  of  oxygen,  and 
also  forms  ozone.    (After  Lockyer.) 

At  a  high  temperature  its  atoms  are  again  dissociated,  and  recombine  to 
form  ordinary  oxygen.  When  it  combines  with  other  substances,  the  heat 
of  combination  appears  to  be  sufficient  to  dissociate  the  atoms  of  ozone  (Oj), 
so  that  in  the  compound  we  meet  with  simple  oxygen,  O. 

When  sulphur  is  simply  melted  and  cooled,  it  solidifies  as  a  yellow 
brittle  substance,  but  if  it  is  heated  to  200°  it  becomes  brownish  and  thick, 
and  if  it  be  suddenly  cooled,  by  throwing  it  into  water,  it  solidifies  as  a  trans- 
parent reddish  plastic  and  elastic  substance.  The  ordinary  brittle  and 
yellow,  and  the  reddish  plastic  sulphur,  appear  to  be  quite  different  sub- 
stances. But  if  the  plastic  sulphur  be  left  for  some  hours,  it  becomes  re- 
converted into  ordinary  sulphur ;  and  if  either  ordinary  or  plastic  sulphur 
be  volatilised,  the  vapour  condenses  in  the  form  of  ordinary  sulphur ;  but  if 
the  vapour  is  quickly  cooled,  the  sulphur,  while  retaining  its  ordinary  appear- 
ance, may  yet  undergo  a  certain  change  evidenced  by  its  becoming  insoluble 
in  bisulphide  of  carbon.  On  the  new  hypothesis  we  explain  these  phenomena 
by  supposing  that  the  different  forms  of  sulphur  are  'different  compounds,  or 
perhaps  we  should  rather  say  different  aggregates,  for  their  components  may 
not  differ  in  kind  like  those  of  calcium,  but  only  in  number  like  those  of 
oxygen  or  ozone. 

Indeed  we  are  almost  driven  to  such  a  conclusion  by  the  behaviour  of 
sulphur  in  regard  to  its  vapour  density,  for  only  at  very  high  temperatures  does 
the  specific  gravity  of  the  vapour  follow  the  general  rule,  and  at  lower  tem- 
peratures it  is  three  times  as  great  as  it  ought  to  be,  indicating  that  at  these 
lower  temperatures  the  molecule  of  sulphur  contains  six  atoms  instead  of  two. 

Phosphorus  also  affords  us  an  example  of  an  element  which  occurs  in 
two  forms,  so  different  that  we  should  call  them  distinct  bodies,  were  it  not 
that  we  find  that  one  can  be  transformed  into  the  other. 

The  two  forms,  red  and  yellow  phosphorus,  differ  from  each  other,  not 
only  in  their  colour,  but  in  their  density,  specific  heat,  readiness  of  com- 
bustion, and  heat  of  combustion.  They  differ  also  in  the  fact  that  yellow 
phosphorus  is  exceedingly  poisonous,  whereas  the  red  phosphorus  is  not 
poisonous.  They  are  in  many  respects,  then,  different  bodies,  but  we  have 
hitherto  been  content  to  call  them  allotropic  forms  of  the  same  element. 

In  combination  we  find  that  phosphorus  is  sometimes  pentad  and  sometimes 
triad ;  that  its  compounds  with  oxygen  are  sometimes  poisonous,  at  other  times 
not.  Thus  orthophosphoric  acid,  H3P04,  is  not  poisonous ;  pyrophosphorio 
acid,  H4P20,,  and  metaphosphoric  acid,  HPOs,  are  both  poisonous. 

The  most  striking  example,  however,  is  carbon,  which  we  not  only  find 


chap,  i.]  GENEEAL  EELATIONS.  15 

in  three  forms,  differing  enormously  from  each  other,  as  diamond,  charcoal, 
and  graphite,  but  which  we  find  in  various  compounds  playing  the  most 
varied  parts.    This  we  at  present  explain  by  saying  that  carbon  unites  with 
itself  in  the  formation  of  the  various  radicals ;  and  thus  comes  to  form  what ' 
are  practically  new  elements. 

Another  example  is  afforded  us  by  ammonia,  the  salts  of  which  are  just  as 
well  characterised  as  those  of  potash  or  soda.  The  amalgam  which  it  forms 
with  mercury  possibly  indicates  that  we  have  in  it  also  a  real  metal, 
ammonium,  corresponding  to  sodium  or  potassium,  though  thiB  is  uncertain. 

The  three  metals,  sodium,  potassium,  and  ammonium  (if  it  exist),  agree  in 
the  readiness  with  which  they  are  oxidised,  so  that  it  is  difficult  to  preserve  the 
•.tire  metal,  although  the  oxide  is  stable.  They  differ,  however,  in  the  oxides 
of  potassium  and  sodium  being  solid,  and  that  of  ammonium  gaseous. 
Ammonium  has  not  been  isolated,  and  it  is  put  down  in  the  text-books  as  a 
hypothetical  substance,  but  ammonium  salts  are  tangible  enough,  and  the 
question  which  we  have  to  keep  before  us  is,  whether  potassium,  sodium, 
and  all  the  other  so-called  elements,  are  not  in  reality  compounds  like 
ammonium. 

Some  people  still  regard  species  as  immutable,  and  look  upon  Darwin's 
hypothesis  of  evolution  as  unproven. 

The  evidence  in  favour  of  the  evolution  of  elements  from  one  simple  form 
of  matter,  is  as  yet,  perhaps,  much  less  strong  than  that  in  support  of  the 
evolution  of  species  ;  but  the  hypothesis  has  this  advantage,  that  it  explains 
certain  phenomena  which  have  hitherto  been  very  perplexing. 

It  may  be  at  least  convenient  in  discussing  the  physiological  action  of 
drugs  to  bear  this  hypothesis  in  mind,  and  to  remember  that  what  we  have 
hitherto  been  accustomed  to  call  elements  may  be  really  constituted  like  the 
so-called  organic  radicals,  with  this  difference,  that  we  can  split  up  organic 
radicals  with  tolerable  facility,  while  we  cannot  do  this — at  least  to  any  great 
extent — with  elements. 

It  also  shows  us  that  we  must  as  pharmacologists  pay  attention  to 
molecular  as  well  as  to  empirical  composition,  and  take  into  consideration 
crystalline  form  and  physical  aggregation  in  all  observations  regarding  the 
relations  between  elements  or  compounds  and  living  organisms.  It  is  not 
sufficient,  for  example,  to  speak  of  the  action  of  phosphorus  on  the  organism 
as  if  this  were  invariable,  for.it  varies  with  the  molecular  composition  of 
the  body  in  the  red  or  yellow  form,  and  isomeric  organic  substances  may  be 
utterly  different  in  action. 

Classification  of  the  Elements. 

The  vegetable  and  animal  kingdoms  are  divided  into  various  groups. 
Formerly,  men  tried  to  arrange  them  in  linear  succession  so  that  there  should 
be  an  unbroken  line  from  the  lowest  to  the  highest  members  of  the  vegetable 
kingdom,  thence  to  the  lowest  member  of  the  animal,  and  onwards  up  to  the 
highest  member  of  the  animal  kingdom.  Such  an  arrangement  as  this, 
however,  was  found  to  be  unnatural.  Instead  of  the  highest  members  of  the 
vegetable  kingdom  being  connected  with  the  lowest  members  of  the  animal 
kingdom,  it  is  found  that  the  lowest  members  of  each  kingdom  are  closely 
connected  and  that  the  divergence  becomes  greater  as  development  proceeds 
towards  the  highest  members  in  each  kingdom.  The  doctrine  of  evolution 
at  once  rendered  this  arrangement  natural  and  easily  understood. 

Starting  from  one  common  point  of  origin  in  structureless  protoplasm, 
the  various  organisms  became  more  and  more  unlike  in  each  successive  stage 
of  development,  their  resemblance  being  only  recognisable  at  all  in  their 
embryonic  condition. 

Various  attempts  have  been  made  to  arrange  inorganic  substances  in 
natural  orders.  One  mode  of  arrangement  is  according  to  their  atomic 
weight — as  in  the  following  table : — ' 

1  In  this  and  the  following  Tables  the  atomic  weights  have  been  corrected. 


10 


PHARMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


a 

ft 

1 

1 

1 

0 

!s 

a 

a 
1 

d 

M 

0) 

a 

t 

a) 

1 

s 

1 

1 

W 
P 

13 

1 

<a 

1 

a 
Si 

a 

1 
a 

! 

5 

o 

a 

V 
-M 

w 

5 

H 

l 

K 

39 

3-5 

Y 

89-8 

2-4 

Ce 

141 

2 

Li 

7' 

6 

Ca 

40 

1 

Zr 

90 

0-2 

Di 

145-4 

3-6 

Gor, 
Be  ! 

Ti 

49-8 

9-8 

Nb 

94 

4 

Ta 

182 

36-6. 

9 

2 

V 

51-3 

1-5 

Mo 

95-5 

1-5 

W 

184 

2 

B 

11 

2 

Cr 

62-5 

1-2 

Eh 

104 

8-5 

Ir 

192-7 

8-7 

0 

12 

1 

Mn 

'55 

2-5 

Eu 

104-2 

0-2 

Pt 

195 

2-3 

N 

14 

2 

Fe 

56 

1 

Pd 

105-7 

1-5 

Au 

196-5 

1-5 

0 

16 

2 

Ni 

58 

2 

Ag 

108 

2-3 

Os 

198-5 

2 

m 

19 

3 

Co 

58-9 

0-9 

Cd 

111-8 

3-8 

Hg 

200 

1-5 

Na 

23 

4 

Cu 

63-4 

4-5 

Sn 

118 

6-2 

Tl 

203-7 

3-7 

Mg 

24 

1 

Zn 

65 

1-6 

Sb 

120 

2 

Pb 

207 

4 

Al 

27 

3 

As 

75 

10 

I 

127 

7 

Bi 

209 

3 

Si 

28 

1 

Se 

78-8 

3-8 

Te 

128 

1 

Th 

233 

24 

P 

31 

3 

Br 

80 

1-2 

Cs 

133 

5 

U 

240 

V 

S 

32 

1 

Bb 

85-3 

5-3 

Ba 

137 

4 

CI 

35-5 

3-5 

Sr 

87-4 

2-1 

La 

139 

2    1 

1 

From  this  it  will  be  seen  that  the  atomic  weights  of  the  different  elements 
form  a  series,  the  members  of  which  in  most  cases  differ  from  one  another  by 
1,  2,  3,  or  4.  There  are  few  exceptions  in  which  the  differences  are  much 
greater,  and  these  probably  represent  blanks  which  may  yet  be  Med  up  as  our 
knowledge  of  the  elements  increases.  This  mode  of  classification,  however, 
reminds  us  of  the  Linnsean  system  in  plants,  and  is  artificial  rather  than 
natural.  In  it,  the  elements  which  are  placed,  close  together  possess  very 
different  properties,  whereas  those  which  are  separated  from  each  other 
present  considerable  resemblances. 

Newlahd's  Tablb. 


Difference 

Member  of  a  Group 
having  Lowest  Equivalent 

One  immediately  above 
the  preceding 

H  =  I 

0  =  1 

Magnesium      .    24 

Calcium  .        .    40 

16 

1 

Oxygen    .        .     16 

Sulphur  .        .    32 

16 

1 

Lithium  .        .      7 

Sodium    .        .    23 

16 

1 

Carbon     .        .    12 

Silicon     .        .    28 

16 

1 

Fluorine  .        .    19 

Chlorine  .        .    35-5 

16-5 

1-031 

Nitrogen  .        .    14 

Phosphorus      .    31 

17 

1-062 

Lowest  term  of  Triad 

Highest  term  of  Triad 

Lithium  .        .      7 

Potassium        .    39 

32 

2 

Magnesium      .    24 

Cadmium         .  112 

88 

5-5 

Molybdenum    .    96 

Tungsten         .  184 

88 

5-5 

Phosphorus      .    31 

Antimony         .  120 

89 

5-687 

Chlorine  .        .    35-5 

Iodine      .        .  127 

91-5 

5-718 

Potassium        .    39 

Caesium   .        .141 

102 

5-875 

Sulphur  .        .    32 

Tellurium        .  128 

96 

6-062 

Calcium  .        .    40 

Barium    .        .  137 

97 

6-062 

CHAP.  I.j 


GENERAL  RELATIONS. 


17 


The  first  important  attempt  at  a  natural  classification  of  the  elements 
•was  made  by  Newlands  in  1864.1  He  then  arranged  them  in  groups,  be- 
tween the  members  of  which  there  was  a  close  connection  in  regard  to  their 
chemical  properties,  and  a  curious  relation  in  regard  to  their  atomic  weights. 
These  presented  differences  which  were  generally  multiples  of  the  atomic 
weight  of  hydrogen,  and  generally  equal  to,  or  multiples  of,  that  of  oxygen. 

A  curious  relationship  had  also  been  pointed  out  by  M.  Dumas  2  between 
the  members  of  the  potassium  group,  their  atomic  weights  being  equal  to 
multiples  of  those  of  lithium  and  potassium  added  together. 

7  +    39  =    46 

7  +     78  =    85 


Li  +    K  =  2Na,    or  in 

Li  +  2K  =    Eb 
2Li  +  3K  =    Cs  (133) ' 

Li  +  5K  =    Tl  (203-7) 
3Li  +  5K  =  2Ag 


14  +  117  =  131 

7  +  195  =  202 

21  +  195  =  216 


A  similar  relation  was  also  pointed  out  by  Mr.  Newlands  between  lithium 
and  the  calcium  group ;  as  follows : — 

Li  +    Ca  =  2Mg  (48),  or  in  figures,  7  +    40  =    47 

Li  +  2Ca  =    Sr  „  7  +    80  =    87 

2Li  +  3Ca  =    Ba  (137)        „  14  +  120  =  134 

Li  +  5Ca  =    Pb  „  7  +  200  =  207 

But  Mr.  Newland's  most  important  table  is  the  following  one,  in  which 
he  has  arranged  the  elements  in  ten  series  : — 


Triad 

Lowest 

Mean 

Highest 

term 

term 

I. 

Li     7 

+  17     =Mg24 

Zn   65 

Cd  111-8 

II. 

B    11 

Au  196 

III. 

C    12 

+  16    =Si  28 

Snll8 

IV. 

N    14 

+  17    =  P    31 

As    75 

Sb  120 

+  88=Bi  210 

V. 

O    16 

+  16    =S    32 

Se    78-8 

Tel28 

+  70  =  Os  199 

VI. 

F    19 

+  16-5  =  C1  35-5 

Br    80 

I    127 

VII. 

Li  7 

+  16  =  Na  23 

+  16    =K   39 

Bb   85-3 

Cs  133 

+  70  =  T1  203 

VIII. 

Li  7 

+  17  =  Mg24 

+  16    =Ca40 

Sr    87-4 

Bal37 

+  70  =  Pb  207 

IX. 

V    51-3 

W  184 

X. 

Mo  95-5 
Pdl05-7 

Pt  195 

Seven  of  these  series  nearly  correspond  in  their  first  members  with  those 
of  Mendelejeff,  to  whom  and  to  Lothar  Meyer  we  owe  the  complete  develop- 
ment of  this  mode  of  classification.  Mr.  Newlands  also  pointed  out  that  the 
eighth  element  starting  from  a  given  one,  was  a  kind  of  repetition  of  the  first, 
like  the  eighth  note  of  an  octave  in  music.4 

Mendelejeff  has  not  only  greatly  developed  this  system  of  classification, 
but  has  afforded  convincing  proof  of  its  value  by  not  only  predicting  the 
existence  of  an  unknown  element,  but  actually  describing  its  physical  cha- 
racters and  chemical  reactions — a  prediction  the  correctness  of  which  was 
proved  by  the  discovery  of  gallium,  and  by  the  agreement  of  its  characters 
and  reactions  with  those  which  Mendelejeff  had  foretold. 

The  various  members  of  the  animal  kingdom  can  all  be  arranged  in  a  few 
series  :  Protozoa,  Coelenterata,  Annuloida,  Annulosa,  Molluscoida,  Mollusca, 
and  Vertebrata.    These  series  all  differ  more  or  less  from  one  another,,  but  a 

1  Newlands,  Chemical  News,  July  30,  1864. 
s  Dumas,  quoted  by  Newlands,  op.  cit. 

*  The  newer  atomic  weights  of  Cs,  Fl,  Mg,  and  Ba  do  not  correspond  so 
exactly  as  their  old  ones  with  the  sum  of  the  other  elements. 

*  Chem.  News,  Aug.  20, 1864,  p.  94. 

C 


18  PHAKMACOLOGY  AND  THEBAPEUTICS.     [sect,  u 

certain  agreement  is  observed  between  their  members,  and  similarly  the 
elements  may  be  arranged  in  series. 

Mendelejeff  points  out,  that  if  we  take  those  elements  having  the  lowest 
atomic  weight,  and  omit  hydrogen,  between  which  and  lithium  there  is  a  great 
gap,  the  seven  elements,  lithium,  glucinum,  boron,  carbon,  nitrogen,  oxygen, 
and  fluorine,  may  be  regarded  as  typical  elements  forming  a  series  repre- 
senting the  lowest  members  of  seven  groups.  The  next  seven  elements  may 
be  arranged  in  a  similar  way : — 

Li  =  7  :  G  =  9-4  :  B  =  11 :  C  =  12  :  N  =  14  :  0  =  16  :  F  =  19  : 
Na  =  23  :  Mg  =  24  :  Al  =  27  :  Si  =  28  :  P  =  31  :  S  =  32  :  CI  =  35-5. 

To  each  group  of  seven  elements  Mendelejeff  gives  the  name  of  a  small 
period  or  series.  In  each  series  the  characters  of  the  elements  vary  gra- 
dually and  regularly  as  their  atomic  weights  increase.  This  variation  is 
periodical,  i.e.  varies  in  the  same  way  in  each  series,  so  that  the  elements 
which  have  corresponding  places  in  each  series,  correspond  also  to  a  certain 
extent  in  their  properties,  and  form  similar  compounds.  The  atomicity  is 
least  in  the  first,  and  greatest  in  the  last  members  of  each  series.  Thus  the 
first  members  of  the  series  form  monochlorides,  the  second  dichlorides,  the 
third  trichlorides,  and  so  on. 

In  the  accompanying  table  B  represents  radical  or  element,  and  B'  indi- 
cates that  the  element  is  monatomic,  so  that  one  atom  combines  with  one  of 
CI  to  form  a  monochloride,  BC1.  E"  indicates  that  the  element  is  diatomic, 
and  so  on. 

But  a  difference  is  to  be  observed  between  the  even  and  the  uneven  series. 
Corresponding  members  of  even  series,  such  as  the  fourth  and  sixth,  agree 
with  each  other,  and  members  of  uneven  series  like  the  fifth  and  seventh  agree. 
This  agreement  is  greater  than  between  the  members  of  an  even  series,  such 
as  the  fourth,  and  those  of  an  uneven  series  like  the  fifth,  although  the  fifth 
is  more  closely  placed  to  the  fourth  than  the  sixth  is.  Thus  Ca  and  Sr 
belonging  to  the  fourth  and  sixth  series  have  a  greater  resemblance  to  each 
other  than  they  have  to  Zn  or  Cd,  which  belong  to  the  fifth  and  seventh  series, 
and  these  metals  on  the  other  hand  have  a  greater  resemblance  to  each  other 
than  they  have  to  Ca  or  Sr.  The  members  of  even  series  are  less  metalloidal 
or  more  metallic  than  those  of  uneven  series,  e.g.  Mn  of  the  fourth  series  is 
less  metalloidal  than  Br  of  the  fifth  series.  In  the  even  series  the  metallic 
or  basic  character  predominates,  whilst  the  corresponding  members  of  the 
uneven  series  rather  exhibit  acid  properties.  The  members  of  the  even  series, 
so  far  as  we  know,  form  no  volatile  compounds  with  hydrogen  or  alcohol 
radicals,  while  the  corresponding  members  of  the  uneven  series  do  form  such 
compounds. 

<  The  last  members  of  the  even  series  resemble  in  many  respects  (in  their 
lower  oxides,  etc.),  the  first  members  of  the  uneven  series;  thus  chromium 
and  manganese  in  their  basic  oxides  are  analogous  to  copper  and  zinc.  But 
there  are  great  differences  between  the  last  members  of  the  uneven  series 
(haloids),  and  the  first  members  of  the  next  even  series  (alkali  metals).  Now 
between  the  last  members  of  the  even  series  there  occur,  according  to  the 
order  of  atomic  weights,  all  those  elements  which  cannot  be  included"  in  the 
small  periods.  Thus  between  Cr  and  Mn  in  the  one  series,  and  Cu  and  Zn 
in  the  next,  there  come  the  elements  Fe,  Co,  Ni,  and  in  a  similar  way  after 
the  sixth  series  come  Eu,  Eh,  Pd,  and  after  the  tenth  Os,  Ir,  Pt.  Mendelejeff 
gives  the  name  of  a  long  period  to  two  such  series  with  three  intervening 
members,  forming  seventeen  in  all. 

From  the  difficulty  of  arranging  all  the  elements  in  this  system,  it  cannot 
be  regarded  as  yet  perfect,  but  the  fact  that  Mendelejeff  was  able  so  correctly 
to  foretell  the  properties  of  gallium,  shows  that  it  must  contain  a  large  ele- 
ment of  truth.  At  the  time  that  he  drew  up  his  table  there  was  a  blank  in 
the  third  group  of  the  fifth  series. 

The  relationships  of  the  metal  which  Mendelejeff  believed  would  fill  this 


CHAP.  I.] 


GENEBAL  RELATIONS. 


19 


jiff 

g     Stf 

S 

Fe  =  56  Co  =  54 
Ni  =  59  Cu*  =  63 

Eu  =  104  Eh  =  104 
Pd  =  106  Ag*  =  108 

Os  =  199  Ir  =  193 
Pt  =  195  Au*=  196 

S 

rH 

ft 

w>                 O                 C-                   I                     1 
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0.H00 

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29  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

gap  will  be  more  easily  seen  by  omitting  the  even  series  on  either  side  of  it, 
and  taking  only  the  odd  series  with  which  it  will,  as  already  mentioned,  the 
more  closely  correspond. 


Series. 

Group  IT. 

Group  III. 

Group  IV. 

Group  T 

3 

Mg 

Al 

Si 

P 

5 

Zn 

— . 

— 

As 

7 

Cd 

In 

Sn 

Sb 

.As  it  stands  between  zinc  with  an  atomic  weight  of  sixty-five,  and  arsenic 
with  one  of  seventy -five,  while  it  is  separated  from  the  latter  by  a  blank,  its 
atomic  weight  must  be  about  sixty-eight.  As  it  is  atom -analogous  with  Al, 
its  salts  should  have  a  similar  constitution.  It  should  form  an  oxide  x203, 
and  a  sulphide  x2Ss.  It  will  be  precipitated  from  its  solution  by  ammonium 
sulphide.  The  metal  should  be  easily  reduced  by  carbon  or  sodium,  it  should 
have  a  specific  gravity  of  5'9,  and  decompose  water  at  a  red  heat.  As  it  be- 
longs to  an  odd  series,  it  should,  like  zinc,  form  volatile  compounds  with 
organic  radicals,  and  form  also  anhydrous  chlorides. 

On  the  discovery  of  the  metal  gallium,  it  was  found  to  agree  in  almost 
every  respect  with  the  prediction  of  Mendelejeff,  and  this  fact  is  not  interest- 
ing to  chemists  only,  but  also  to  pharmacologists.  For  the  great  object  of 
pharmacology  is  to  obtain  such  a  knowledge  of  the  relations  between  the 
physical  and  chemical  characters  of  bodies,  and  their  actions  upon  the  living 
organism,  that  we  may  be  able  to  predict  their  actions  with  certainty,  and 
to  know  the  modifications  which  alterations  in  their  physical  and  chemical 
characters  will  produce  on  their  physiological  action. 

Mendelejeff  s  present  classification  is  imperfect,  because  we  find  that  by 
it  the  members  of  some  natural  groups,  such  as  those  of  the  earthy  metals,  are 
separated  from  one  another,  although  they  agree  in  their  chemical  characters. 

We  find  also  that  metals  having  similar  pharmacological  actions,  as 
copper,  zinc  and  silver,  do  not  fall  naturally  together  in  this  arrangement. 
But,  on  the  other  hand,  we  find  also  that  by  this  classification,  elements  are 
brought  .together  which  do  not  at  first  seem  to  have  any  resemblance  to  each 
other,  and  are  yet  found  by  recent  investigations  to  have  a  physiological  con- 
nection. Thus  mercury  and  calcium  do  not  appear  to  resemble  one  another, 
yet  Prevost  has  shown  that,  in  acute  poisoning  by  mercury,  the  calcareous 
matter  disappears  from  the  bones,  and  in  the  process  of  elimination  by  the 
kidneys  produces  calcification  of  these  organs.1 

Organic  Radicals.— Whether  the  so-called  elements  be 
compounds  or  not,  it  is  certain  that  several  of  them  have  the 
power  of  uniting  with  themselves  and  with  others  in  such  a 
way  as  to  form  bodies  called  compound  radicals  which  resemble 
elements  in  many  respects.  These  groups  of  atoms  may  enter 
into  and  again  pass  out  of  combination  with  other  substances, 
just  as  elements  do. 

For  example,  when  compounds  of  the  elements  unite,  an 
interchange  of  elements  takes  place.  Thus  when  calcium  oxide 
(CaO)  and  hydrochloric  acid  (HC1)  combine,  the  oxygen  leaves 
the  calcium  to  combine  with  the  hydrogen  and  form  water,  while 
the  chlorine  leaves  the  hydrogen  and  combines  with  the  calcium 
to  form  calcium  chloride. 

CaO  +  2HCl  =  CaCl2  +  H20. 


1  Prevost,  Eevuo  MMicale  de  la  Suisse  Bomande,  p.  553,  Nov.  15  •  t>    605 
Dec.  15,  1882  ;  p.  5,  Jan.  15,  1883.  '  *"        ' 


CHAP.  I.] 


GENEEAL  EELATIONS. 


21 


But  when  ethylic  alcohol  (C?H60)  is  treated  with  hydrochloric  acid 
(HC1),  it  is  not  oxygen  which  leaves  the  alcohol  and  is  replaced 
by  chlorine.  The  alcohol  does  not  split  up  into  the  group  C2H6 
and  the  element  oxygen,  but  into  the  two  groups  OH  and  C.JIS. 

C2H60  +  HC1  =  C2HaCl  +  H20 ; 
or,  as  it  may  also  be  represented — 

(^^)@)  +  hci = C5?T) ci+H  ©■ 

To  the  group  OH  the  name  of  hydroxyl  has  been  given,  and 
to  the  group  C2H5  that  of  ethyl. 

Similarly,  when  acetic  acid  (C2H402)  is  treated  with  phos- 
phorus trichloride  (PC13)  the  three  atoms  of  chlorine  leave  the 
phosphorus,  and  are  replaced  by  three  hydroxyl  (OH)  groups. 

3  C2H402  +  PC13  =  3  C2H3O01  +  PO3II3 ; 

or,  as  it  might  be  represented — 


+© 


+    P 


OH" 

oih 


This  mode  of  representation  is  awkward  and  cumbrous,  although 
it  is  clear,  and  the  same  reactions  may  be  represented  more 
shortly,  thus : 

3  C2H30.  0H  +  PC13  =  3  C2H30.  Cl  +  P  .  (0H)3. 

Here  again  it  is  not  oxygen,  but  hydroxyl  (OH),  which 
breaks  off  from  the  acetic  acid,  just  as  it  did  from  alcohol ;  but 
instead  of  the  group  C2H6  (ethyl)  being  left  behind,  we  have 
another  group,  C2H30  (acetyl). 

It  is  evident  that  such  groups  of  atoms  or  radicals,  as  they 
are  termed,  as  hydroxyl,  ethyl,  acetyl,  &c,  behave  in  combina- 
tion just  like  elements.     They  are  not  known  in  a  free  state. 

In  order  to  exhibit  the  valency  and  probable  relationships  of 
radicals,  they  are  sometimes  expressed  by  graphic  formulas,  in 
which  the  affinities  are  shown  by  a  — ,  as  well  as  in  the  ways 
already  shown. 

As  the  position  of  the  radicals  in  some  compounds,  e.g.  in 
the  organic  alkaloids,  is  probably  of  great  importance  in  regard 
to  their  action,  although  the  subject  is  not  well  understood  at 
present,  the  most  important  radicals  are  given  below,  with  their 
graphic  as  well  as  their  ordinary  formula. 

Hydroxyl,  OH,  or  —  0— H.  This  is  a  monad  radical, 
consisting  of  one  atom  of  dyad  oxygen,  —0—,  with  one  of  its 


22  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

two  affinities  saturated  by  an  atom  of  hydrogen,  and  the  other 
affinity  free.  It  was  at  one  time  called  water-residue,  as  it  is 
the  residue  left  after  the  removal  of  one  atom  of  hydrogen  from 
water,  which  may  be  regarded  as  the  hydride  of  the  radical. 

Hydroxyl  is  an  important  constituent  of  alcohols,  regarding 
the  chemical  constitution  of  which  two  views  may  be  taken. 
They  may  either  be  looked  on  as  water  in  which  one  atom  of 
hydrogen  is  replaced  by  organic  radicals,  or  as  compounds 
of  the  radicals  with  hydroxyl.  Tbe  constitution  of  water  and 
alcohol  may  be  represented  graphically,  K  standing  for  a  monad 
organic  radical — 

H-O-H  water; 

E-O-H  alcohol,  e.g.,    (Ethyl}  -O-H  ;    (Phenyl)  -O-H 

Ethyl-alcohol.  Phenyl-alcohol,  or 

Phenol. 

The  presence  of  the  hydroxyl  group  in  certain  substances, 
and  also  its  position  in  them,1  appear  to  be  of  great  importance 
in  regard  to  their  physiological  action.2    , 

By  replacing  the  hydrogen  in  one  atom  of  hydroxyl  by  a 
monad,  or  in  two  atoms  by  a  dyad  element,  other  radicals  are 
formed,  e.g. 

Potassoxyl,  KO,  or  —  0— K. 

Zincoxyl,  OZnO,  or  —  0\ 

_o>n- 

When  united  to  carbonyl,  hydroxyl  forms  a  very  important 

radical  carboxyl. 

* 

Carbonyl,    CO   or    —  C  — ,  is  a  dyad  radical  consisting  of 

II 

0 
tetrad  carbon,  in  which  two  affinities  are  saturated  by  dyad 
oxygen,  and  two  left  free.  It  exists  in  aldehydes,  ketones,  and 
acids,  although  in  aldehydes  it  is  combined  with  hydrogen,  and 
in  acids  with  hydroxyl,  to  form  other  radicals.  In  ketones  both 
its  free  affinities  are  saturated  by  organic  radicals,  which  may 
either  be  of  the  same  kind  or  of  different  kinds. 


E-C-E,e.£r.(Methyl)-C-(iJethyl)  (Thenyh-C-(MethyT) 

II  ^ ^      II     V ^ ^     II        

0  0  0 

Acetone.  Phenyl-methyl-acetone. 

Aldehyde  Group,  CHO,  or  -C-H.    When  the  free  affinity 

II 
0 

1  Efron,  PflUger's  Arcfoiv,  xxxvi.  p.  467. 

8  Stolnikow,  Zeitschr.f.physiol.  Ohem.,  1884,  viii.  pp.  235  and  271. 


chap,  i,]  GENEEAL  EELATIONS.  23 

of  this  group  is  saturated  by  a  monatomic  radical,  we  get  alde- 
hydes; thus — 

(JthyT)-C-H  ,  (^nyj)  -C-H 


0 

0 

Ethyl-aldehyde. 

Benzoic  aldehyde 

(oil  of  bitter  almonds). 

Carboxyl,    CO.OH,   or    Ci}}  0,  or  -C-O-H.    This  is 

HI  j 

0 

a  monad  radical.  When  its  free  affinity  is  saturated  by  an 
organic  radical,  it  forms  monad  organic  acids,  in  which  the 
hydrogen  of  the  hydroxyl  is  readily  replaced  by  a  basic  element. 

E_C-H-0,e.^.(lSethyl)  -C-O-H  (fhlnyT) -C-O-H 

II  ^ ^      II  II 

0  0  0 

Acetic  acid.  Benzoic  acid. 


rMeti^l)_C-0-Na    (Ph^nyT)-C-0-Na 

^     II  II 

0  0 

Sodium  acetate.  Sodium  benzoate. 

Carbon  forms  an  immense  number  of  radicals  by  union 
with  itself  and  with  hydrogen,  e.g. 

H    H 
H  H    H  || 

I  I      I  /C-C\ 

H   C-  H-C-C-    h-c/      nyc- 

I  I      I  ,". 

H  HH  H    H 

Methyl.  Ethyl.  Phenyl. 

Nitrogen  gives  origin  also  to  a  number  of  most  important 
radicals. 


Nitroxyl,  NOa. 

2,  or 
•H 


/H 
Amidogen,  NH2,  or  —  N^     • 


Imidogen,  NH  or  N^ 


24  PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

Phosphorus,  arsenic,  and  antimony  give  origin  also  to  a 
number  of  radicals  similar  to  those  of  nitrogen. 

PH2,  or  -P^;   SbHa,  or  -Sb^;  AsH2,  or  -As<^H 

/H  /H  /H 

PH,  or  -P/     ;    SbH,  or  -Sb^     ;   AsH,   or  -As<^ 

Sulphur  also  gives  origin  to  some  important  radicals. 


0  /yO 

;a\    I  ;  Sulphin,  SO,  or  -Sf 


Sulphuryl  (sulphon),  S02,  or  J>S<    I  ;  Sulphin,  SO,  or  -S<f 


Chemical    Reactions    and    Physiological    Reactions.— 

Each  element  and  each  of  its  compounds  has  chemical  re- 
actions special  to  itself,  by  which  it  can  be  recognised  and  dis- 
tinguished from  all  others.  The  number  of  these  chemical 
reactions  is  therefore  very  great,  but  there  are  a  few  reactions 
which  are  common  to  a  great  number  of  the  elements.  We 
shall  find  that  something  similar  occurs  in  their  physiological 
reactions. 

The  number  of  possible  actions  which  may  be  exerted  on  the 
body  by  the  elements  and  their  compounds  is  very  great,  yet  we 
shall  find  that  there  are  certain  physiological  reactions  which  are 
common  to  so  many  that  their  repetition  under  the  head  of  each 
drug  becomes  monotonous. 

Chemical  Reactions. — Although  the  chemical  reactions 
of  the  metallic  elements  are.  numerous  and  varied,  yet  there 
are  certain  reactions  which  are  common  to  a  very  large  number, 
and  by  these  the  class  of  metallic  elements  may  be  subdivided 
into  sub-classes.  Other  reactions  again  are  common  to  a  few 
elements  only,  and  by  these  the  sub-classes  may  be  subdivided 
into  groups.  Other  reactions  again  are  peculiar  to  each 
individual  element,  and  by  them  it  may  be  distinguished  from 
all  others. 

Thus,  by  the  use  of  hydrogen  sulphide,  or  ammonium 
sulphide,  we  at  once  divide  the  class  of  metallic  elements  into 
two  sub-classes : 

A.  Metals  which  give  a  precipitate  with  one  or  other  of  these 
reagents. 

B.  Metals  which  give  no  precipitate  with  either. 

Physiological  Reactions.— It  is  probable  that,  if  our  know- 
ledge of  physiological  chemistry  were  sufficient,'  we  might  be 
able  to  classify  physiological  reactions  according  to  the  chemical 
relation  between  substances  introduced  into  the  organism  and 
the  various  constituents  of  the  organism  itself.    At  present  we 


chap,  i.]  GENERAL  RELATIONS.  25 

are  quite  unable  to  do  this ;  but,  as  albuminous  substances  form 
an  essential  part  of  all  living  organisms,  we  may  roughly  divide 
the  elements  physiologically,  by  their  relation  to  albumen,  just 
as  we  do  it  chemically,  by  their  relation  to  sulphur,  into  two 
sub- classes: 

A.  Those  which  precipitate  albumen. 

B.  Those  which  do  not. 

Just  as  in  the  case  of  sulphides,  we  might  further  sub-divide 
sub-class  A  into  two  sections : 

(a)  Those  which  precipitate  albumen  in  acid  solutions. 

(&)  „  „  „  in  neutral  or  alkaline 

solutions. 

Section  (b)  may  be  further  sub-divided  into  groups  according 
to  the  kind  of  albuminous  bodies  which  its  members  precipitated, 
e.g.,  myosin,  globulin,  serum-albumen,  albumoses,  peptones,  &c. 

We  might  also  divide  sub-class  B  in  two  sections : 

(a)  Substances  which,  though  they  do  not  precipitate  albu- 
men, have  a  marked  affinity  for  fatty  substances  or  other  con- 
stituents of  the  organism,  and  especially  of  the  nervous  system 
(p.  144). 

(b)  Substances  having  no  such  action. 

It  is  evident  that  such  a  classification  as  this,  although  it 
might  form  the  groundwork  of  a  system  to  be  perfected  at  some 
future  time,  is  at  present  so  imperfect  that  it  is  generally  more 
convenient  to  divide  physiological  reactions  according  to  the 
organs  affected :  e.g.,  muscles,  nerve-centres,  respiration,  circu- 
lation, secretion,  &c. 

A.  This  group  contains  substances  which  paralyse  muscles 
and  motor  nerves.  The  number  of  these  substances  is  very  great 
(p.  126  et  seq.,  p.  150). 

This  large  group  can  again  be  subdivided  into  those  which 
(a)  paralyse  muscle,  while  affecting  the  nerves  but  slightly,  or 
(6)  paralyse  the  nerves  and  leave  the  muscle  uninjured. 

B.  Another  large  group  is  that  which  acts  specially  on  nerve- 
centres,  and  has  little  effect  either  on  muscles  or  motor  nerves. 
This  contains  sub-groups  of  substances  which  affect  the  brain, 
medulla,  or  spinal  cord  by  exciting,  paralysing,  or  disturbing  the 
functions  of  each. 

C.  Another  group  is  that  which  affects  the  secretions,  with 
sub-groups  of  substances  affecting  the  secretions  from  the  sweat 
and  mammary  glands,  salivary,  gastric,  or  intestinal  glands,  liver, 
or  kidneys. 

D.  Another  group  still  is  that  which  acts  chiefly  upon  the 
circulation. 

These  groups  are  all  more  or  less  distinct,  although  they,  tp 
a  certain  extent,  may  run  into,  or  overlap,  each  other. 

Individual  members  of  the  same  group  may  differ  very  widely 
in  their  physiological  action,  even  when  they  all  finally  paralyse 


2(1  PHABMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

muscle,  nerves,  and  nerve-centres.  For  while  they  may  pro- 
duce the  same  final  result,  the  course  of  their  action  will  be 
different,  and  the  symptoms  they  occasion  will  depend  very 
greatly  upon  the  part  of  the  organism  which  they  affect  first. 
Thus  atropine  and  curare  both  completely  paralyse  motor  or 
efferent  nerves,  but,  while  a  very  large  dose  of  curare  is  required 
to  paralyse  the  cardiac  and  vascular  nerves,  a  very  small  dose 
paralyses  those  going  to  the  muscles,  and  produces  increasing 
weakness,  gradually  passing  into  death.  On  the  other  hand, 
an  enormous  dose  of  atropine  is  required  to  paralyse  the 
motor  nerves  of  muscles,  but  very  small  doses  are  sufficient 
to  affect  the  nerves  of  the  heart  and  other  involuntary  muscles, 
and  thus  we  get  rapid  circulation,  dilated  pupil,'  and  restless 
delirium. 

The  physiological  action  of  any  drug  depends  to  a  great 
extent,  not  merely  on  its  general  affinities  for  classes  of  tissues, 
but  upon  its  particular  affinity,  or  power  of  acting  on  one  tissue 
or  organ  first.  The  organ  first  affected  may,  through  its  func- 
tional activity,  greatly  alter  the  effects  of  the  drug  upon  the 
others. 

As  an  example  of  this  we  may  take  the  effects  produced  by 
very  large  and  by  moderate  doses  of  veratrine  on  the  frog.  A 
moderate  dose  will  produce  great  stiffness  of  the  muscles,  while 
a  very  large  dose  may  have  comparatively  little  effect.  Yet  if 
the  large  dose  were  applied  directly  to  the  muscles  it  would  act 
more  powerfully  than  the  moderate  dose.  The  reason  that  it 
does  not  do  so  in  the  living  body  is  that  the  large  dose  paralyses 
the  heart  so  quickly  that  the  circulation  stops,  and  therefore  the 
poison,  not  being  conveyed  to  the  muscles,  has  no  action  upon 
them. 

Relation  between  Isomorphism  and  Physiological 
Action. — From  a  number  of  experiments  made  by  Dr.  Blake, 
he  concluded  that  when  inorganic  salts  were  injected  directly 
into  the  circulation,  the  intensity  of  their  physiological  action 
increased  in  proportion  to  their  molecular  weight,  but  only  in 
those  groups  of  elements  where  the  salts  were  isomorphic,  or  in 
other  words,  crystallised  in  the  same  forms.  Thus  groups  whose 
salts  were  crystallised  in  different  forms  had  quite  different 
physiological  actions.  He  adopts  Mitscherlich's  division  of  the 
elements  into  nine  groups,  and  considers  that  the  physiological 
action  of  the  different  groups  differs  in  kind,  whilst  that  of  the 
individual  members  of  the  same  group  agrees  in  kind  but  differs 
in  degree.  Thus  he  states '  that  the  salts  of  the  first  group 
increase  in  activity  in  the  order  mentioned,  silver  being  the  most 
active,  and  lithium  the  least. 

1  Blake,  American  Journal  of  Science  and  Arts,  vol.  vii.,  March  1874  (corrected 

reprint). 


chap,  i.]  GENERAL  EELATIONS.  27 

These  groups  are  as  follows : — 

Group  1.  Lithium,  sodium,  rubidium,  thallium,  caesium,  and  silver. 
According  to  him  they  produce  death  by  acting  on  the  lungs  and  impeding 
the  pulmonary  circulation.  None  of  them  affect  the  nervous  system  excepting 
cassium ;  nor  do  any  affect  the  pulmonary  circulation  excepting  silver. 

Group  2.  Magnesia,  ferrous  salts,  manganous  salts,  nickel,  cobalt,  copper, 
zinc,  and  cadmium  are  increasingly  lethal  in  the  order  mentioned.  They 
kill  by  arresting  the  action  of  the  heart. 

Group  3.  Beryllium,  alumina,  yttria,  cerium,  and  ferric  salts  both  impede 
the  systemic  and  pulmonary  circulation. 

Group  4.  Calcium,  strontium,  barium,  and  lead  salts  kill  by  paralysing 
the  ventricles  of  the  heart. 

Group  5.  Palladium,  platinum,  osmium,  and  iridium  act  on  the  heart, 
respiration,  circulation,  and  blood. 

Group  6.  Ammonia  and  potash  paralyse  the  heart  and  cause  convulsions. 

Group  7.  Hydrochloric,  hydriodic,  bromic,  and  iodic  acids  impede  the 
circulation  and  kill  by  arresting  the  circulation. 

Group  8.  Phosphoric  acid,  arsenic  acid,  and  antimony  kill  by  arresting 
the  pulmonary  circulation. 

Group  9.  Sulphuric  and  selenic  acid  impede  the  pulmonary  circulation. 

The  author's  statements  regarding  the  mode  of  action  of  the 
elements  show  that  their  physiological  action  has  not  been  fully 
investigated,  and  his  results  as  to  the  lethal  dose  are  probably 
only  approximate  and  may  want  re-investigation ;  but  while  we 
cannot  accept  at  present  all  his  results  or  conclusions  as  final, 
yet  his  last  and  chief  conclusion  is  one  of  great  interest — viz., 
that  in  living  matter  we  possess  a  reagent  capable  of  aiding  us 
in  our  investigations  on  the  molecular  properties  of  substances. 

Relation  between  Spectroscopic  Characters  and 
Physiological  Action. 

The  quickness  with  which  a  pendulum  oscillates  is  less  or  greater  accord- 
ing to  its  length,  a  long  one  oscillating  slowly,  and  a  short  one  quickly.  The 
vibrations  of  a  string  or  pipe  are  also  slow  or  quick,  and  the  note  which  it 
yields  is  low  or  high,  according  as  it  is  long  or  short. 

Similarly,  according  to  Lecoq  de  Boisbaudran,  the  rate  of  vibrations  of 
molecules,  and  the  wave-lengths  of  the  light  which  they  emit,  are  determined 
by  their  weight.  When  the  molecular  weight  is  high,  the  vibrations  of  the 
molecules  are  slow,  and  the  light  which  they  emit  has  long  wave-lengths,  and 
is  situated  towards  the  red  end  of  the  spectrum.  When  the  weight  is  low 
the  vibration  of  the  molecules  is  rapid ;  and  the  light  they  emit  lies  towards 
the  violet  end  of  the  spectrum. 

In  the  same  family  of  elements  the  mean  length  of  the  wave  of  light 
which  they  emit  is  a  function  of  their  atomic  weight,  so  that  for  bodies  of  the 
same  chemical  type  the  general  form  of  the  spectrum  persists,  but  is  gradually 
modified  by  the  mass  of  the  molecules.  As  the  atomic  weight  diminishes, 
the  spectrum  will  tend  to  ascend  towards  the  violet,  and  as  it  increases  the 
spectrum  will  tend  to  descend  towards  the  red. 

Until  recently,  our  observations  on  the  spectra  of  bodies  were  limited  to 
the  visible  spectrum,  but  the  application  of  photography  now  enables  us 
to  extend  our  observations  both  above  and  below  the  visible  spectrum,  and 
to  ascertain  the  presence  of  definite  spectra  in  the  ultra-red  and  ultra-violet, 
when  nothing  of  the  sort  is  visible  to  the  eye.  In  most  musical  sounds 
besides  the  fundamental  note  we  have  a  number  of  harmonics  having  a  much 
greater  rapidi,ty  of  vibration  than  it.  Similarly,  in  the  spectrum  there  appear 
harmonics  as  well  as  the  fundamental  spectral  lines,  and  so  instead  of  one 


28  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  r. 

line  or  band  there  may  be  a  number.  According  to  the  author  already  quoted, 
the  corresponding  harmonics  in  a  series  of  analogous  spectra  have  mean 
wave-lengths  which  increase  in  proportion  to  the  weight  of  the  molecules. 

It  might  appear,  therefore,  that  a  relation  might  be  observed  between  the 
spectroscopic  characters  and  physiological  action  of  an  element,  and  this 
idea  was  propounded  by  Papillon.  His  idea  was,  however,  to  a  great  extent 
based  on  the  experiments  of  Eabuteau  referred  to  later  on,  and  just  as  no 
definite  relation  can  be  at  present  traced  between  the  atomic  weight  and  the 
toxic  action  of  a  metal,  so  no  definite  relation  can  be  observed  between  its 
spectroscopic  characters  and  its  physiological  action. 

Further  consideration,  however,  will  show  us  that  this  is  not  at  all  to  be 
wondered  at,  for  in  physiological  experiments  we  are  not  working  with  the 
same  molecules  which  yield  the  spectrum. 

In  spectrum-analysis,  when  line  spectra  are  in  question,  according  to  one 
view  we  are  in  presence  of  phenomena  produced  by  the  chemical  atom, 
whereas  this  atom  exists  only  molecularly  combined  at  lower  temperatures. 
According  to  another  view,  that  put  forward  by  Lockyer,  we  are  in  presence 
of  phenomena  produced  by  a  series — possibly  a  long  series — of  simplifications, 
brought  about  by  the  temperature  employed,  and  this  simplification  can 
begin  at  very  low  temperatures,  and  is  indeed  indicated  by  Dalton's  law  of 
multiple  proportions. 

Such  molecular  simplifications  and  differences  are  represented  by  ozone 
and  oxygen,  ordinary  and  amorphous  phosphorus,  the  various  forms  of  sul- 
phur and  so  on,  and  it  is  therefore  at  this  lower  range  of  temperature — where 
the  phenomena  are  to  be  studied  by  absorption,  and  not  by  radiation — that 
we  must  look  for  connections  between  molecular  structure  and  physiological 
action  if  any  such  connection  exists.1 

Some  of  the  absorption  bands  which  occur  in  the  spectra  of  bodies  at 
ordinary  temperatures  may  be  in  the  visible  spectrum,  like  those  observed  in 
alcoholic  and  aromatic  substances  ; 2  but  others  may  be  quite  invisible,  and 
only  recognisable  by  the  aid  of  photography  in  the  ultra-red  or  ultra-violet.3 

Relation  between  Atomic  Weight  and  Physiological 

Action. 

From  experiments  made  on  the  toxic  action  of  the  chloride,  bromide,  and 
iodide  of  potassium,  Bouchardat  and  Stewart  Cooper  came  to  the  conclusion 
that  a  relation  existed  between  the  physiological  activity  of  elements  and 
their  atomic  weight,  the  activity  being  inversely  as  their  atomic  weight,  e.g. 
fluorine  (atomic  weight,  19)  being  more  active  than  chlorine  (atomic  weight, 
35-5). 

In  1867,  Kabuteau  made  a  number  of  experiments  from  which  he  con- 
cluded that  Bouchardat  was  correct  in  saying  that  the  physiological  activity 
of  the  monatomic  metalloids  was  in  inverse  proportion  to  their  atomic  weight, 
while  that  of  the  diatomic  metalloids  increased  directly  with  their  atomic 
weight :  selenium  being  more  active  than  sulphur. 

He  considered  also  that  he  had  discovered  a  new  law  regarding  the  re- 
lation between  the  atomic  weight  and  the  physiological  activity  of  metals : 
viz.,  that  the  activity  of  metals  increases  with  their  atomic  weight.  He 
afterwards  qualified  this  statement  by  saying  that  the  poisonous  action  in- 
creased with  the  atomic  weight  amongst  elements  belonging  to  the  same 
group.  Thus  potassium  (atomic  weight,  39)  is  more  poisonous  than  sodium 
(23),  and  barium  (137)  than  calcium  (40).  But  it  has  been  shown  by  Huse- 
mann  that  lithium  is  much  more  poisonous  than  sodium,  and  his  results 
have  been  confirmed  by  Bichet. 

In  the  following  table  the  lethal  activity  of  various  metals  is  given  aa 

1  See  Hartley,  Phil.  Trams.,  Part  II.  1885. 

'  Eussell  and  Lapraik,  Journ.  Chetn.  Soc,  April  1881. 

•  Abney  and  Testing,  Phil.  Trans.,  1882,  p.  887. 


CHAP.  I.] 


GENERAL  RELATIONS. 


29 


determined  by  Bichet,  and  of  the  metals  belonging  to  the  groups  of  the  alkalis 
and  earths  as  determined  by  Bichet,  by  Cash  and  myself,  and  by  Botkin,  jun. 
Where  the  position  of  the  metals  in  the  tables  is  different  the  symbols  are 
printed  in  italics.  The  most  active,  Hg,  is  first ;  the  least  active,  Na  or  Ca,  last. 


Kichet 

Brunton 

Botkin, 

Atomic 

Kichet 

Brunton 

Botkin, 

Atomic 

and  Cash 

junr. 

Weight 

and  Cash 

junr. 

Weight 

Hg 





200 



Cs 

Cs 

133 

Cu 

— 

— 

63-4 

Li 

Li 

Li 

7 

Zn 

— 

— 

65 

Mn 

— 



55 

Fe 

— 

— 

56 

Ba 





137 

Cd 

— 

— 

111-2 

Mg 

— 

— 

24 

NSt 

— 

— 

18 

— 

La 

— 

139 

K 

K 

K 

39 

— 

Di 

— 

145-4 

— 

Be 

— 

9 

— 

Er 



163 

— 

Bb 

Bb 

85-3 

Sr 

Sr 



87-4 

Ni 

— 

— 

58 

— 

Yt 

— 

89-8 

Co 

_ 

— 

58 

Ca 

Na 

— 

40123 

— 

Ba 

— 

137 

Na 

Ca 

— 

23|40 

— 

NHt 

— 

18 

Eichet's  experiments  were  made  upon  fish,  and  the  substances  were 
added  to  the  water  in  which  the  animals  were  swimming.  The  experiments 
of  Cash  and  myself  were  made  upon  frogs,  and  the  substances  were  injected 
subcutaneously.  Botkin's  experiments  '  were  made  upon  dogs,  and  the  sub- 
stances were  injected  directly  into  the  circulation. 

It  is  possible  that  the  differences  observed  were  due  to  the  differences  in 
the  animals  on  which  the  experiments  were  made,  or  in  the  way  of  applying 
the  poison.  Botkin's  table,  so  far  as  it  goes,  agrees  perfectly  with  Cash's  and 
mine,  and  there  is  a  general  correspondence  also  between  Eichet's  results  and 
ours,  although  there  are  several  differences  in  particulars. 

It  is  thus  evident  that  the  relationship  between  atomic  weight  and  physio- 
logical action  is  no  simple  one.  But  indeed,  on  looking  into  the  matter  more 
closely,  we  could  hardly  expect  it  would  be.  For  the  toxic  action  of  an 
element  may  depend  upon  its  effect  on  the  muscles,  nerves,  nerve-centres, 
blood,  or  on  the  digestive  or  excretory  systems.  These  differ  from  one 
another  in  their  composition,  and  while  it  is  possible  that  the  elements 
belonging  to  a  certain  group  may  have  relations  varying  with  their  atomic 
weight  to  individual  organs  or  structures,  we  can  hardly  expect  those  rela- 
tionships to  be  the  same  to  all  organs. 

Thus  an  element  with  one  atomic  weight  may  prove  fatal,  by  affecting 
the  muscular  power  of  an  animal,  while  another  with  an  atomic  weight  either 
higher  or  lower,  may  be  still  more  deadly  by  affecting  the  nervous  system  or 
heart. 

What  we  want,  therefore,  is  not  a  general  relationship  between  atomic 
weight  and  toxic  action,  but  a  knowledge  of  the  particular  relationships  ot 
each  group  of  elements  to  each  organ  and  tissue  of  the  body. 

Relation  of  Atomic  Weight  and  Smell. 

The  idea  has  been  put  forward  by  Eamsay  that  the  sense  of  smell  is 
excited  by  vibrations  of  a  lower  period  than  those  which  give  rise  to  the 
sense  of  light  or  heat.    These  vibrations  are  conveyed  by  gaseous  molecules 


1  S.  Botkin,  junr. :  '  Zur  Frage  fiber  den  Zusammenhang  der  physiologischen 
Wivkung  mit  den  chemischen  Eigenschaften  der  Alkalimetalle  der  ersten  Grappa 
nach  Mendelejeff,'  Centralb.  filr  die  med,  WissenscJiaft.  No.  48  1885. 


30  PHARMACOLOGY  AND  THERAPEUTICS,     [sbot.i.- 

to  the  surface  network  of  nerves  in  the  nasal  cavity.  The  difference  of 
smells  is  caused  by  the  rate  and  by  the  nature  of  such  vibrations,  just  as 
difference  in  tone  of  musical  sounds  depends  upon  the  rate  and  on  the  nature 
of  the  vibration— the  nature  being  influenced  by  the  number  and  pitch  of  the 
harmonics.  Just  as  the  eye  and  ear  are  capable  only  of  appreciating  sight  or 
sound  vibrations  occurring  within  a  limited  range,  bo  the  nose  is  unable  to 
appreciate  a  smell  the  result  of  the  rapid  vibrations  produced  by  substances  of 
low  molecular  weight.  Hydrocyanic  acid  appears  to  be  at  the  lowest  limit,  as 
one  in  five  are,  according  to  him,  unable  to  detect  its  odour.  It  is  fifteen  times 
the  molecular  weight  of  hydrogen,  and  he  concludes  that  to  produce  the  sensa- 
tion of  smell  a  substance  must  have  a  molecular  weight  at  least  fifteen  times 
that  of  hydrogen.  The  intensity  of  smell  in  bodies  of  similar  constitution  in- 
creases with  the  molecular  weight ;  thus,  methyl-alcohol  is  odourless,  but  the 
intensity  of  smell  increases  with  the  molecular  weight  of  each  succeeding 
member  of  the  alcohol  group,  until  the  limit  of  volatility  is  reached,  and 
they  become  changed  into  solids  with  such  a  low  vapour  tension  that  they 
give  off  no  appreciable  amount  of  vapour  at  the  ordinary  tension.1 

Relation  of  Atomic  Weight  to  Taste. 

Haycraft  considers a  that  '  quality '  in  taste  depends  upon  the  nature  of 
the  atoms  found  in  the  sapid  molecule.  A  study  of  the  periodic  law  demon- 
strates that  similar  tastes  are  produced  by  combinations  which  contain 
elements  such  as  lithium,  sodium,  potassium,  which  show  a  periodic  recur- 
rence of  ordinary  physical  properties.  Among  the  carbon  compounds,  those 
which  produce  similar  tastes  are  found  to  contain  a  common  'group'  of 
elements.  Thus  organic  acids  contain  the  group  CO.OH,  the  sweet  sub- 
stances CHe.OH.  There  is  no  relation  between  quality  of  sensation  and 
gross  molecular  weight,  except  that  substances  of  either  very  small  or  very 
great  molecular  weight  are  not  tasted  at  all. 

Connection  between  Chemical  Composition  and 
Physiological  Action. 

In  considering  this  subject  and  other  subjects  allied  to  it, 
we  must  carefully  distinguish  between  chemical  composition  and 
chemical  constitution ;  between  the  mere  elements  of  which  a  com- 
pound is  formed  and  the  manner  in  which  these  elements  are  put 
together.  Thus  the  cyanides,  or  nitriles,  and  the  isonitriles,  or 
carbamines,  both  contain  carbon  and  nitrogen,  and  contain  them 
in  equal  proportions ;  but  the  manner  in  which  the  carbon  is 
united  with  the  nitrogen  probably  differs  in  the  two  classes,  and 
their  physiological  action  is  different.  Tneir  chemical  composition 
is  the  same,  but  their  chemical  constitution  is  different. 

It  was  pointed  out  by  Blake  in  1841  that  a  close  connection 
exists  between  the  chemical  constitution  and  physiological  action 
of  salts ;  their  physiological  action  on  animal  organisms  appear- 
ing to  depend  chiefly  on  the  base.  Yet  the  physiological  action 
of  any  salt  is  not  dependent  entirely  upon  the  base\  It  may  be, 
and  sometimes  is,  modified  to  a  very  great  extent  by  the  acid  ; 
moreover,  we  find  that  the  salts  which  the  same  inorganic  base 

1  Nature,  June  22,  1S82,  p.  187. 

2  Ibid.,  Oct.  8,  1885,  p.  562. 


CHAP.  I.] 


GENERAL  RELATIONS. 


31 


may  form  with  different  acids  may  present  very  different  physio- 
logical actions,  as  in  the  case  of  the  carbonate,  bromide,  and 
cyanide  of  potassium.  The  same  is  the  case  with  organic  bases, 
and  Richardson,  in  1865,  drew  attention  to  an  example  of  the 
relation  between  the  action  of  the  base  and  acid  in  the  amyl 
compounds.  He  found  that  amyl-hydride  had  an  anaesthetic 
effect ;  the-  introduction  of  oxygen,  as  in  amyl-alcohol  or  amyl- 
acetate,  added  spasm  to  this  action ;  amyl-iodide  produced  a 
large  excretion  of  fluid  from  the  body,  while  amyl-nitrite  had 
a  great  effect  on  the  circulation.  Thus,  the  base  remaining 
the  same,  different  acid  radicals  modified  the  action  of  the  com- 
pound.1 

The  fact  is  that  sometimes  the  action  is  determined  chiefly 
by  the  base  (whether  it  be  inorganic  or  organic),  and  sometimes 
chiefly  by  the  acid.  The  action  of  the  whole  salt  may  differ  to  a 
great  extent  from  that  of  the  substances  composing  it,  and  it 
may  agree  to  some  extent  with  other  salts,  which  differ  from  it 
both  in  regard  to  the  base  and  acid  composing  them ;  thus — the 
sulphate  of  magnesium  and  the  sulphate  of  sodium  are  both  pur-, 
gative,  and  in  this  property  they  agree  not  only  with  the  sulphate 
of  potassium,  in  which  the  base  is  different  although  the  acid  is 
the  same,  but  with  the  bitartrate  of  potassium,  in  which  both 
the  base  and  the  acid  are  different.  This  fact  confirms  what  has 
already  been  said  regarding  the  necessity  for  taking  into  con- 
sideration crystalline  form  and  physical  aggregation,  as  well  as 
chemical  composition  (p.  15). 

Physiological  Action  of  the  Constituents  of  a  Drug. — In 
the  case  of  acids  and  bases,  the  physiological  action  of  each  is 
modified  by  their  union,  e.g.  when  caustic  soda  and  hydrochloric 
acid  unite,  the  caustic  action  of  each  is  destroyed,  and  we  obtain 
sodium  chloride  and  water,  which  have  different  physiological 
actions,  as  well  as  different  chemical  characters,  from  either  the 
acid  or  the  base. 

But  if  we  examine  a  series  of  salts  of  the  same  base  with 
different  acids,  or  of  the  same  acid  with  different  bases,  we  find 
that  both  the  acid  and  the  base  modify  the  physiological  action 
of  the  compound. 


Different  Acids.                                          Different  Bases. 

Sodium 

hydrate 

caustic.                         Sodium     ichloride 

neutral  in  action. 

» 

bicarbonate 

antacid.                        Potassium 

ii 

muscular  poison. 

i) 

sulphate 

purgative.                     Zinc 

ii 

caustic. 

i) 

benzoate 

antilitMc.                     Barium 

ii 

muscular  poison. 

„ 

salicylate 

antipyretic.                   Silver 

>» 

inert. 

it 

cyanide 

powerful  poison.          Iron 

ii 

astringent, 

hcematinic. 

Mercuric 

ii 

corrosive,     anti- 
septic. 

This  modification  is  in  some  cases  due  to  a 

change  in  the 

Brit.  Assoc.  Reports,  1865,  p.  280. 


32  PHAEMACOLOGY  AND   THERAPEUTICS,     [sect.  I. 

physical  conditions,  and  especially  in  the  soluhility  of  the  com- 
pound. Thus  the  chloride  of  silver  is  inert  so  long  as  it  remains 
in  the  form  of  a  chloride,  because  it  is  insoluble.  It  thus  differs 
much  from  the  corrosive  chloride  of  zinc,  while  if  we  were  to 
compare  the  action  of  the  nitrate  of  silver  and  zinc  we  should 
find  considerable  similarity. 

Another  cause  of  difference  is  the  different  proportion  of  the 
acid  to  the  base. 

Thus  the  proportion  of  sodium  (Na=23)  to  the  acid  radical 
in  the  following  sodium  salts  is  as  follows :  in  the  hydrate 
as  23  to  18 ;  in  the  bicarbonate  as  23  to  61 ;  in  the  sulphate  as 
23  to  96 ;  in  the  benzoate  as  23  to  121 ;  in  the  salicylate  as  23 
to  137. 

In  this  connection,  too,  the  degree  of  saturation  of  the  acid 
by  the  base  must  be  considered.  If,  for  example,  the  acid  is  not 
saturated,  part  of  the  action  of  the  compound  is  due  to  its  acid 
chemical  properties ;  and  if,  on  the  other  hand,  a  weak  acid  be 
combined  with  a  strong  base,  this  action  is  partly  due  to  the 
alkaline  chemical  property. 

Relation  between  Physiological  Action  and  Chemical 
Constitution. 

An  immense  step  has  been  made  of  late  years  in  our 
knowledge  of  the  relation  between  chemical  constitution 
and  physiological  action  by  the  discoveries  of  Crum-Brown, 
Fraser,  and  Schroff,  who  have  shown  that  by  modifying  artifi- 
cially the  chemical  constitution  of  a  drug  it  is  possible  to  modify, 
also  its  physiological  action.  And  not  only  so,  but  they  have 
shown  that  similar  modifications  in  the  chemical  constitution 
of  various  drugs  induce  similar  modifications  in  the  action  of 
their  derivatives ;  thus  they  have  found  that  by  introducing 
methyl  into  the  molecule  of  strychnine,  brucine,  and  thebaine, 
the  convulsive  action  exerted  by  these  substances  on  the  spinal 
cord  was  changed  into  a  paralysing  one  exerted  on  the  ends  of 
the  motor  nerves.  Other  alkaloids,  also,  which  do  not  exhibit 
a  convulsive  action,  nevertheless  exhibit  a  paralysing  one  when 
their  constitution  is  altered  by  means  of  methyl ;  thus  methyl- 
codeine,  methyl-morphine,  methyl-nicotine,  methyl-atropine, 
methyl-quinine,  methyl-veratrine,  and  several  others,  all  exhibit 
this  paralysing  action  (p.  150). 

As  a  general  rule,  most  of  the  compound  radicals  formed  by 
the  union  of  amidogen  with  the  radicals  of  the  marsh-gas  series 
possess  a  paralysing  action  on  motor  nerves. 

The  subject  of  the  connection  between  chemical  constitution 
and  physiological  action  is  the  most  important  one  in  phar- 
macology, and  we  shall  have  to  return  to  it  in  considering  the 
actions  of  various  groups  of  organic  substances. 


33 


CHAPTEE  IL 

CIRCUMSTANCES  WHICH  AFFECT  THE  ACTION  OF 
DRUGS  ON  THE   ORGANISM. 

One  of  the  most  important  circumstances  affecting  the  action  of 
any  drug  is  the  mode  in  which  it  is  brought  into  contact  with 
the  various  parts  of  the  organism. 

Local  and  Remote  Action. — The  local  action  of  a  drug  is 
that  which  it  exerts  on  the  part  to  which  it  is  applied.  Thus 
sulphuric  acid  has  a  direct  irritant  or  destructive  action,  and 
when  applied  to  the  skin  or  mucous  membrane  will  produce 
local  redness,  inflammation,  or  sloughing.  When  swallowed, 
it  produces  weakness  of  the  circulation,  stoppage  of  the  heart, 
and  death. 

This  effect  on  the  circulation  is  not  due  to  the  direct  action 
of  the  acid  upon  the  heart,  the  vessels,  or  the  nervous  system, 
after  its  absorption :  it  is  due  to  the  reflex  action  exerted  upon 
them  by  the  irritation  of  the  nerves  of  the  stomach  which 
the  sulphuric  acid  produces.  This  action  on  different  parts 
through  the  nervous  system  is  termed  its  remote  action,  in 
contradistinction  to  the  local  action  of  the  acid  upon  the  gastric 
mucous  membrane. 

The  Interaction  of  various  functions  in  the  body  is  one 
of  the  greatest  difficulties  in  the  way  of  our  readily  understanding 
the  action  of  drugs. 

One  function  alters  another,  and  the  second  reacts  upon  the 
first,  so  that  in  some  cases  it  is  almost  impossible  to  say  precisely 
how  far  the  alteration  in  any  function  is  due  to  the  direct  effect 
of  the  drug  upon  it,  and  how  far  to  some  indirect  action.  Thus 
curare  when  applied  to  a  wound  usually  kills  without  producing 
any  convulsion  whatever.  It  paralyses  the  ends  of  the  motor 
nerves,  so  that  all  the  muscles  in  the  body  become  powerless. 
But  when  it  is  given  by  the  stomach,  and  excretion  through 
the  kidneys  prevented,  death  is  preceded  by  convulsions.  These 
convulsions  are  not  caused  by  any  direct  irritating  action. of  the 
curare  itself  upon  the  nerve-centres ;  they  are  due  to  irritation  of 
these  centres  by  a  venous  condition  of  the  blood.  This  venosity 
of  the  blood  is  due  to  imperfect  respiration,  produced  by  paralysis 


34  PHAEMACOLOGY   AND  THEEAPEUTICS.      [sect.  i. 

of  the  respiratory  muscles  through  the  action  of  curare  on  the 
motor  nerves.1 

The  effect  of  curare  is  a  purely  paralysing  one,  both  when 
the  animal  dies  quietly  and  when  it  dies  with  convulsions.  In 
both  cases  it  paralyses  the  motor  nerves  of  the  respiratory 
muscles  and  of  the  extremities.  In  both  cases  it  causes  death 
by  arresting  the  respiration  and  producing  asphyxia.  But  in 
the  latter  case  the  motor  nerves  of  the  extremities  being  only 
partially  paralysed  when  asphyxia  occurs,  they  respond  by  con- 
vulsive movements  to  the  irritation  of  the  nerve-centres,  which 
the  venous  blood  produces.  In  the  former,  the  paralysis  of  the 
limbs  being  complete,  the  muscles  remain  perfectly  quiet,  not- 
withstanding the  irritation  of  the  nerve-centres. 

Convulsions  also  sometimes  occur  previous  to  death  from 
narcotic  poisons:  and  in  a  description  of  the  action  of  these 
poisons  we  frequently  meet  with  the  phrase,  '  coma,  convulsions, 
and  death.'  In  such  cases  the  convulsions  are  also  caused  by 
the  irritation  of  the  nerve-centres  by  asphyxial  blood. 

The  drug  causes  the  coma;  the  coma  causes  imperfect  re- 
spiration ;  imperfect  respiration  renders  the  blood  venous ;  and 
tne  venous  blood  causes  convulsions. 

Direct  and  Indirect  Action. — The  direct  action  of  a  drug 
is  the  effect  it  produces  on  any  organ  with  which  it  comes  in 
contact.  Thus  sulphuric  acid  applied  to  the  skin,  or  taken 
into  the  stomach,  will,  according  to  its  degree  of  concentration, 
irritate  or  destroy  the  mucous  membrane  which  it  touches. 
Its  direct  action  upon  them  is  therefore  that  of  an  irritant  or 
caustic. 

Curare,  when  applied  to  the  ends  of  a  motor  nerve  in  a 
muscle,  paralyses  them.  It  does  this  either  when  the  muscle 
is  soaked  in  a  solution  of  curare,  or  when  the  curare  is  carried 
through  the  substance  of  the  muscle  by  means  of  the  blood 
circulating  in  it. 

Paralysis  is  therefore  the  direct  effect  of  curare  on  the  motor 
nerves. 

The  convulsions  which  sometimes  occur  in  poisoning  by 
curare  are  caused  by  its  indirect  action.  It  has  no  stimulating 
effect  on  the  nerve-centres,  when  applied  to  them  directly  or 
caried  to  them  by  the  blood,  but  by  paralysing  the  muscles  of 
respiration,  and  thus  causing  asphyxia,  it  indirectly  irritates  the 
nerve-centres,  and  causes  convulsions. 

Selective  Action  of  Drugs. — Drugs  sometimes  seem  to 
affect  only  one  part  of  the  body  and  to  leave  the  other  organs 
unaffected ;  although  the  drugs  may  be  carried  equally  by  the 
blood  to  every  part  of  the  body,  they  appear  to  combine  with 
some  and  not  with  others.     Many  dye-stuffs  will  not  attach 

■  Hermann,  Arch.}.  Aitat.  U.  Physiol,  1807,  64,  650. 


Chap,  ii.]    ACTION  OF  DBTJGS  ON  THE  ORGANISM.  85 

themselves  to  cotton  fabrics,  but  will  do  so  readily  to  wool  or 
silk ;  and  we  find  that  different  tissues,  and  even  different  parts 
of  the  same  tissue,  have  very  unequal  attractions  for  stains : 
thus  some  anilin  colours  will  deeply  stain  a  nucleus,  while 
leaving  the  cell  in  which  it  is  contained  entirely  uncoloured. 
Although  the  different  organs  of  the  body  contain  many  sub- 
stances in  common,  yet  their  chemical  composition  varies  within 
wide  limits,  and  the  products  of  the  tissue-waste  are  also  differ- 
ent. Even  in  the  same  organs  the  cells  may  have  different 
properties,  and  even  individual  parts  of  the  same  cell  may  differ. 
Some  have  a  reducing,  and  others  an  oxidising  action ;  some  an 
alkaline,  and  others — as  may  be  ascertained  from  their  action  on 
anilin  colours l — an  acid,  reaction  (p.  70) .  We  would  therefore 
expect  that,  just  as  the  tissues  exert  a  selective  action  upon  dye- 
stuffs  which  we  are  able  to  see,  they  will  also  have  a  selective 
action  on  many  organic  substances,  although  this  action  may 
not  be  visible  to  our  senses. 

Primary  and  Secondary  Action. — I  have  already  stated 
(p.  5)  that  the  so-called  action  of  a  drug  is  not  one-sided :  it 
is  the  reaction  between  the  drug  and  the  organism.  While 
drugs  are  circulating  in  the  body  they  may  modify  the  chemical 
nature  and  the  physiological  functions  of  various  organs.  In 
some  cases  the  drug,  after  doing  this,  may  again  leave  the  organs 
and  be  eliminated  without  undergoing  any  essential  change ;  but 
in  other  cases  the  chemical  character  of  the  drug  itself  under- 
goes an  essential  change  during  its  sojourn  in  the  body.  Some 
organic  substances  undergo  complete  combustion,  and  are  con- 
verted into  carbonates,  while  others  are  converted  into  substances 
having  a  powerful  physiological  action,  but  perfectly  different 
from  that  of  the  substance  originally  introduced  into  the  body. 
These  products  of  the  decomposition  of  the  drug  may  then, 
while  circulating  in  the  blood,  or  during  the  process  of  excretion, 
exert  upon  the  organism  a  marked  physiological  action  quite 
different  from  that  of  the  original  substance.  Perhaps  one  of 
the  most  marked  examples  of  this  is  to  be  found  in  morphine. 
Morphine  lessens  the  irritability  of  nerve-centres,  producing 
sleep,  and  having  a  marked  sedative  action  upon  the  stomach 
in  allaying  vomiting,  either  when  introduced  directly  into  the 
stomach  or  injected  into  the  circulation.  This  is  its  primary 
action ;  but  in  the  body  morphine  undergoes  certain  alterations 
and  becomes  partly  converted  into  oxy-dimorphine,  which 
appears  to  counteract  the  soporific  action  of  morphine,  and 
probably  either  oxy-dimorphine  or  some  other  product  of  the 
decomposition  of  morphine  has  an  emetic  action.  The  effect  of 
these  secondary  products  will  manifest  itself  after  the  original 

'  P.  Ehrlioh,  '  Ueber  die  Methylenblaureaotion  der  lebenden  Nervensubstanz.' 
Deutsche  med.  Wochenschrift,  1886,  No.  4.    Ibid.  1885. 

D  2 


86  PHARMACOLOGY  AND  THERAPEUTICS,     [sect,  ft 

dose  of  morphine  has  either  been  eliminated  or  undergone  con- 
version into  the  products  already  mentioned;  and  thus  the 
secondary  action  -will  be  quite  different  from  the  primary,  and 
instead  of  narcosis  and  quietness  of  the  stomach,  there  will  be 
excitement,  and  nausea  or  vomiting,  which  may  require  to  be 
again  counteracted  by  a  larger  dose  of  the  original  drug. 

It  is  evident  that  the  relation  between  the  primary  and 
secondary  effects  of  a  drug  will,  if  this  explanation  be  correct, 
vary  very  much  according  to  the  relative  solubility  of  the  drug 
originally  administered,  and  of  the  products  of  its  decomposition. 
If  the  products  of  decomposition  be  more  soluble,  and  more 
readily  eliminated,  than  the  drug  itself,  they  will  leave  the 
organism  before  it,  and  their  action  will  hardly  appear ;  but  if 
they  are  less  soluble,  and  more  slowly  eliminated,  their  action 
may  persist  for  a  considerable  length  of  time. 

Relation  of  Effect  to  Quantity  of  the  Drug.  —The  effect 
of  drugs  varies  very  much  according  to  the  quantity  employed. 
Sometimes  this  is  due  to  the  interaction  of  different  parts  of 
the  body  on  one  another,  as  already  mentioned  in  regard  to 
veratrine  (p.  26).  Sometimes  it  is  due  to  the  different  effects 
upon  individual  cells  or  tissues.  Thus  we  find,  very  generally, 
that  any  substance  or  form  of  energy,  whether  it  be  acid  or 
alkali,  heat  or  electricity,  which  in  moderate  quantity  increases 
the  activity  of  cells,  destroys  it  when  excessive. 

But  varying  doses  do  not  always  produce  opposite  effects. 
We  sometimes  find  that  exceedingly  small  and  exceedingly 
large  doses  have  a  similar  effect,  which  differs  from  that  pro- 
duced by  moderate  doses.  Thus  very  minute  quantities  of 
atropine  render  the  pulse  somewhat  slow ;  larger  quantities 
make  it  exceedingly  rapid,  and  very  large  quantities  again 
render  it  slow. 

Moderate  quantities  of  digitalis  slow  the  pulse,  larger  quan- 
tities quicken  it,  and  still  larger  quantities  render  it  slow 
again.  We  find  a  similar  effect  produced  by  variation  in  tem- 
perature. Great  cold  disturbs  the  mental  faculties,  so  that 
men  exposed  to  it  present  symptoms  which  cannot  be  dis- 
tinguished from  those  of  intoxication.  Ordinary  temperatures 
do  not  disturb  the  functions  of  the  brain,  but  high  temperatures 
do,  as  we  see  in  the  delirium  of  fever,  which  in  many  cases  im- 
mediately ceases  when  the  temperature  of  the  patient  is  reduced 
by  cold  baths. 

Homoeopathy. — This  opposite  action  of  large  and  small 
doses  seems  to  be  the  basis  of  truth  on  which  the  doctrine  of 
homoeopathy  has  been  founded.  The  irrational  practice  of  giving 
infinitesimal  doses  has  of  course  nothing  to  do  with  the  principle 
of  homoeopathy—  similia  similibus  curantur:  the  only  requisite  is 
that  mentioned  by  Hippocrates,  when  he  recommended  man- 
drake in  mania ;   viz.  that  the  dose  be  smaller  than  would  be 


chap,  ii.]    ACTION  OF  DEUGS  ON  THE  OEGANISM.  87 

sufficient  to  produce  in  a  healthy  man  symptoms  similar  to 
those  of  the  disease.  Now  in  the  case  of  some  drugs  this  may 
be  exactly  equivalent  to  giving  a  drug  which  produces  symptoms 
opposite  to  those  of  the  disease ;  and  then  we  can  readily  see 
the  possibility  of  the  morbid  changes  being  counteracted  by  the 
action  of  the  drug,  and  benefit  resulting  from  the  treatment. 
For  example,  large  doses  of  digitalis  render  the  pulse  extremely 
rapid,  but  moderate  ones  slow  it.1  The  moderate  administration, 
when  there  is  a  rapid  pulse,  is  sometimes  beneficial :  this 
might  be  called  homoeopathic  treatment,  inasmuch  as  the  dose 
administered  is  smaller  than  that  which  would  make  the  pulse 
rapid  in  a  healthy  man ;  but  it  might  also  be  called  antipathic, 
inasmuch  as  the  same  dose  administered  to  a  healthy  person 
would  also  slow  the  pulse. 

Homoeopathy  can  therefore  not  be  looked  upon  as  a  universal 
rule  of  practice,  and  the  adoption  of  any  such  empirical  rule 
must  certainly  do  harm  by  leading  those  who  believe  in  it  to 
rest  content  in  ignorance  instead  of  seeking  after  a  system  of 
rational  therapeutics. 

Dose. — The  amount  of  a  drug,  which  actually  comes  in  con- 
tact with  and  affects  the  tissues,  depends  upon  several  conditions 
— (1)  the  quantity  actually  given ;  (2)  its  proportion  to  the 
body-weight;  (3)  the  rapidity  of  its  absorption  by  the  blood 
from  the  place  of  introduction ;  (4)  the  condition  of  the  circula- 
tion in  various  parts  of  the  body,  which  determines  the  quantity 
of  the  drug  carried  to  each ;  (5)  the  rate  of  its  absorption  by  the 
tissues ;  (6)  the  rapidity  of  excretion. 

The  word  dose,  as  employed  in  medicine,  usually  means  the 
quantity  given  at  one  time,  but  sometimes  this  may  be  very 
different  from  what  actually  produces  any  effect.  It  is  the 
amount  of  the  drug  existing  in  the  blood  at  any  given  time, 
or  rather  the  proportion  of  it  that  actually  comes  in  contact 
with  or  is  absorbed  by  the  tissues,  which  really  acts.  We  must 
therefore  consider  more  in  detail  the  circumstances  which  affect 
this  proportion. 

Size. — As  the  action  which  a  drug  has  on  the  body  is  not 
dependent  on  its  absolute  amount,  but  on  the  proportion  it  bears 
to  the  body  on  which  it  is  to  act,  an  amount  which  is  a  small 
dose  for  one  person  is  a  very  large  one  for  another.2  Thus  if  a 
grain  of  some  active  substance  be  injected  at  the  same  time  into 
the  veins  of  a  full-grown  man  and  into  those  of  a  boy  of  only 
half  his  weight,  it  will  be  distributed  through  twice  as  much 
blood  in  the  man  as  in  the  boy,  and  each  tissue  will  only  receive 
half  as  much  of  it.  The  dose  of  a  drug  must  therefore  be  re- 
gulated by  the  weight  of  the  patient;  and  thus  women,  being 

1  Vide  Traube,  Med,  Centr.  Ztg.  xxx.  p.  94,  1861,  and  Brunton  On  Digitalis,  p.  21. 
2  Buchheim,  Arznevrmttellehre,  3rd  edit.  p.  54. 


38  PHARMACOLOGY  "AND  THERAPEUTICS,     [sect.  I* 

lighter,  require  a  smaller  amount  than  men,  and  children  less 
than  adults.  Though  it  would  be  more  exact,  it  is  not  always 
convenient,  to  weigh  patients;  but  in  experiments  on  animals 
we  usually  weigh  the  animal  carefully,  and  describe  the  dose  in 
terms  of  the  body-weight.  For  example,  in  describing  the  lethal 
dose  of  physostigmine  we  do  not  say  that  it  is  so  many  grains  for, 
an  animal,  but  that  it  is  0*04  grain  per  pound  weight  of  a  rabbit. 
This  relation,  however,  is  not  always  an  exact  one,  and  other 
circumstances  must  be  taken  into  account.  Thus  the  species 
of  the  animal  must  be  considered,  for  the  same  dose  which 
would  kill  one  kind  of  animal  will  not  kill  another.  In  animals 
of  the  same  species  the  state  of  nutrition  must  be  taken  into 
account,  for  two  animals  of  the  same  species,  which  would  be 
nearly  of  the  same  size  when  equally  nourished,  may  have  very 
different  weights  if  the  one  is  fat  and  the  other  is  lean.  But  the 
fat  is  a  comparatively  inert  tissue,  and  if  we  give  to  each  animal 
a  dose  regulated  by  its  body-weight,  the  vital  organs,  brain, 
heart,  and  spinal  cord  of  the  fat  animal  will  get  a  larger  share 
in  proportion  than  those  of  the  lean  one. 

In  testing  the  action  of  poisons  on  frogs,  also,  it  must  be 
remembered  that  a  female  frog  with  a  quantity  of  spawn  will  be 
very  heavy,  but  the  spawn,  like  the  fat,  is  not  to  be  reckoned  as 
tissue  ;  so  that  a  dose  given  in  proportion  to  the  actual  weight 
would  be  much  larger  than  the  same  proportion  given  to  the 
frog  after  spawning. 

Mode  of  Administration. — If  a  substance  be  injected  into 
the  veins,  the  whole  of  it  mixes  with  the  blood  and  becomes 
active  immediately,  and  the  maximum  effect  is  thus  at  once 
obtained  and  will  again  diminish  as  the  substance  is  excreted. 
But  the  case  is  different  if  it  be  injected  subcutaneously,  and  if 
it  be  given  by  the  stomach  or  any  other  mucous  cavity  the 
difference  is  still  greater ;  for  as  soon  as  some  of  it  is  absorbed 
excretion  begins,  and  thus  one  portion  of  the  drug  is  passing  out 
of  the  blood  while  another  portion  is  being  taken  in.  The 
amount  in  the  blood  is,  then,  only  the  difference  between  that  ab- 
sorbed and  that  excreted  in  a  given  time  (Fig.  6).  Absorption  may 
be  so  slow,  or  excretion  so  quick,  that  there  is  never  a  sufficient 
amount  of  the  substance  in  the  blood  to  produce  any  effect. 
Thus  Bernard  found  that  a  dose  of  curare  which  would  certainly 
paralyse  an  animal  when  injected  into  the  veins,  or  even  sub- 
cutaneously, would  have  no  effect  when  introduced  into  the 
stomach ;  '  and  showed  that  this  was  due  to  the  kidneys  ex- 
creting the  poison  as  fast  as  it  was  absorbed  from  the  stomach, 
oy  extirpating  the  kidneys,2  when  the  animal  became  paralysed 
art  surely  as  if  the  poison  had  been  introduced  at  once  into  the 


1  Bernard,  Leqons  sur  les  Effeta  des  Substances  Toxigv.es,  p.  2S2. 
1  Bernard,  Revue  des  Cows  Scientifiques,  1865. 


chap,  ii.]    ACTION  OF  DEUGS  ON  THE  OBGANISM. 


39 


veins,  though  not  so  quickly.  Hermann  also  discovered,  without 
being  acquainted  with  Bernard's  observations,  that  curare  taken 
into  the  stomach  would  produce  paralysis  if  excretion  were  pre- 
vented by  ligature  of  the  renal  vessels. 


Pulmonary  arteries.  >• 
(Absorption.) 

Veins  of  general  surface  of  - 
body.     (Absorption,) 


Liver.  m 

(Destruction  of  drugs.) 

Veins  of  stomach., 

X  Absorption  from  stomach.) 

Biliary  circulation.  ,-..— 
(Excretion  into  intestine.) 

Veins  of  intestine.  — *"" 
(Absorption  from 
intestine.) 


Arteries  going  to  nerve- 
centres. 

Pulmonary  veins. 
(Excretion.) 

Arteries  to  muscles. 


Arteries  to  stomach. 
(Excretion  into  stomach.) 


Arteries  to  intestines. 
(Excretion  into  intestines.) 
Kidney. 


Excretion  by  kidney. 


Fig.  5.— Diagram  to  illustrate  absorption  and  excretion.  The  arrows  show  the  direction  of  the  cur- 
rents. The  absorbents  from  which  the  blood  passes  directly  into  the  general  circulation  are 
represented  diagrammatically  by  the  veins  of  the  lungs  and  of  the  general  body  surface  in  the 
figure.  The  absorbents  by  which  the  drug  must  pass  through  the  liver,  and  possibly  be  partly 
excreted  or  destroyed,  are  represented  by  the  veins  of  the  stomach  and  intestine.  The  exereting 
channels  by  which  the  drug  may  pass  directly  from  the  body  without  re-absorption  occurring 
are  represented  by  the  vessels  of  the  lung  and  by  the  ureter.  Those  by  which  excretion  takes 
place  into  cavities  from  which  much  re-absorption  may  occur  are  represented  by  the  arteries  to 
the  intestine  and  the  stomach. 

The  absorption  of  drugs  from  the  stomach  and  intestines 
may  be  considerably  retarded,  and  their  action  diminished,  by 
the  liver.  Before  reaching  the  general  circulation,  drugs  ab- 
sorbed from  the  intestinal  canal  must  all  pass  through  the  liver 
(Fig.  5).  In  their  passage  they  may  be  partly  arrested  and  ex- 
creted again  into  the  intestine  along  with  the  bile.  They  may 
be  also  partially  destroyed.  A  larger  quantity  of  a  drug  may  thus 
be  necessary  to  produce  similar  effects  when  introduced  by  the 
stomach  than  when  injected  directly  into  the  circulation  or  under 
the  skin — (1)  because  it  may  be  absorbed  more  slowly  by  the 
vessels  of  the  gastric  or  intestinal  mucous  membrane ;  (2)  because 
a  part  of  it  may  be  arrested  in  the  liver  and  excreted  into  the 
intestine  along  with  the  bile ;  (3)  because  a  part  of  it  may  be 
actually  destroyed  in  the  liver. 

The  more  rapid  the  absorption,  or  the  slower  the  excretion, 
of  any  drug,  the  greater  will  be  its  effect.  Thus  the  effect  pro- 
duced by  the  same  dose  of  a  medicine  will  be  in  proportion  to 
the  rapidity  of  its  absorption  from  the  different  parts  to  which  it 
has  been  applied,  unless  the  differences  be  so  slight  that  there 
has  not  been  time  for  the  excretion  of  any  considerable  quantity 
from  the  blood  during  the  process.  On  this  account  we  must 
diminish  the  dose  of  a  medicine  in  order  to  obtain  the  'same 
effect,  according  to  the  rapidity  of  absorption  from  the  place  to 
which  we  apply  it.  Absorption  is  quickest  from  serous  mem- 
branes, next  from  intercellular  tissue,  and  slowest  from  mucous 


10 


PHARMACOLOGY  AND  THERAPEUTICS,     [sect. 


membranes.     The  vascularity  and  rate  of  absorption  from  inter- 
cellular tissue  is  greater  on  the  temples,  breast,  and  inner  side 


Pig.  6.— Diagram  to  illustrate  the  differences  produced  in  the  amount  of  a  drug  present  in  the 
organism  by  alterations  in  the  rate  of  absorption  and  excretion.  The  lower  funnel  represents 
the  organism.  A  represents  the  condition  when  a  drug  is  rapidly  introduced,  as  by  injection 
into  a  vein.  In  this  case  the  drug,  e.g.  curare,  comes  to  be  present  in  large  quantities  in  the 
organism,  and  produces  its  full  physiological  effect.  This  is  represented  by  the  fulness  of  the 
lower  funnel.  And  it  does  this  notwithstanding  the  rapidity  of  excretion,  which  causes 
the  drug  to  be  quickly  eliminated  and  to  appear  copiously  in  the  urine,  as  represented  by  tbe 
fulness  of  the  beaker  into  which  the  fluid  flows  from  the  lower  funnel.  B  represents  the  con- 
dition when  a  drug  is  slowly  absorbed  and  rapidly  excreted,  as  when  curare  is  given  by  the 
stomach.  In  this  case  the  quantity  present  in  the  hlood  at  any  one  time  is  very  minute,  as 
represented  by  the  empty  condition  of  the  lower  funnel.  0  represents  the  condition  when 
absorption  is  rather  quicker  than  excretion,  as  when  a  dose  of  morphine  is  given  by  the  stomach. 
D  represents  the  condition  where  absorption  is  moderate  but  excretion  is  interfered  with,  lead- 
ing to  accumu!  ation  in  the  blood,  as  where  an  active  drug  is  given  by  the  mouth  and  the  kidneys 
are  much  degenerated. 

of  the  arms  and  legs  than  on  their  outer  surfaces,  or  on  the  back.1 
It  should  not  be  forgotten  that  any  drug  introduced  into  the 
stomach,  but  not  absorbed  into  the  blood,  is  as  much  outside 
the  body  as  if  it  were  in  the  hand,  for  any  effect  it  will  have  on 


too.  7,— Diagrammatio  representation  of  the  body,  A  is  a  box  to  represent  the  tissues.  B  is  an 
inner  tube  to  represent  the  intestinal  canal.  It  is  obvious  that  anything  which  is  merely  in  the 
inner  tube  is  outside  the  box,  and,  similarly,  anything  which  is  merely  in  the  intestinal  canal  is 
outside  the  body. 

the  system,  provided  always  it  have  no  local  action  on  the  gastric 
walls.  But  if  it  act  directly  on  the  walls  of  the  stomach,  it  may 
have  an  effect  which  it  would  not  have  when  held  in  the  hand 


Eulenburg,  Hypodermatische  Injection  der  Arzneimittel,  3rd  edit.  p.  65. 


chap.  ii.]    ACTION  OF  DEUGS  ON  THE  OEGANISM.  41 

or  applied  to  the  skin.  Thus  mustard,  which  would  produce 
redness  and  burning  of  the  skin,  will  cause  vomiting  when 
swallowed;  but  opium,  which  does  not  act  on  the  stomach 
itself,  except  by  diminishing  its  sensibility,  produces  no  apparent 
effect  until  after  it  has  been  absorbed. 

By  the  difference  between  absorption  and  excretion  under 
different  circumstances  or  in  different  individuals,1  the  cumu- 
lative action  of  drugs,  the  effect  of  idiosyncrasy,  habit,  climate, 
condition  of  body,  as  fasting,  &c,  disease,  and  form  of  adminis- 
tration, can,  to  a  certain  extent,  though  not  entirely,  be  explained; 
but  experiments  on  some  of  these  points  are  deficient,  and  the 
explanations  now  given  are  to  some  extent  theoretical. 

Duration  of  Action  of  Drugs. — When  a  soluble  drug  is 
introduced  into  the  stomach,  it  will  undergo  absorption,  and  the 
whole  of  it  may  possibly  be  absorbed  without  any  portion  of  it 
even  passing  into  the  intestine.  After  absorption  into  the  blood 
it  will  either  remain  in  the  plasma  or  form  a  compound  with  the 
corpuscles.  It  will  thus  be  carried  to  the  liver,  where  part  of  it 
may  be  retained  (vide  p.  39).  Such  portions  as  pass  through 
the  liver  will  then  be  carried  to  the  right  side  of  the  heart,  to 
the  pulmonary  circulation,  and  then,  passing  to  the  left  side  of 
the  heart,  will  be  distributed  to  all  parts  of  the  body.  As  ab- 
sorption continues,  the  quantity  of  the  drug  in  the  stomach  will 
gradually  diminish,  while  that  in  the  circulation  will  increase  to 
a  certain  extent ;  this  extent,  however,  will  depend  upon  the 
activity  of  the  eliminating  organs.  The  drug  will  be  carried  to 
all  parts  of  the  body,  both  to  the  eliminating  organs  and  to  those 
connected  with  the  other  functions  of  the  organism.  It  will  enter 
into  combination,  more  or  less  firm,  with  all  those  organs  which 
have  any  attraction  for  it,  and  will  more  or  less  modify  their 
functional  activity.  In  the  processes  of  tissue-change,  which  are 
constantly  going  on,  the  combination  between  the  drug  and  the 
organs  will  be  gradually  destroyed  ;  and,  being  again  returned  to 
the  circulation,  it  will  undergo  gradual  elimination.  The  method 
in  which  elimination  occurs  will  also  depend,  to  a  certain  extent, 
on  the  selective  action  of  the  eliminating  organs  ;  thus  soluble  sub- 
stances are  usually  eliminated  most  readily  by  the  kidneys,  while 
salts  of  the  heavy  metals,  which  form  insoluble  compounds  with 
albumen,  are  eliminated  to  a  great  extent  by  mucous  membranes. 

Cumulative  Action. — If  a  substance  be  naturally  so  slowly 
excreted  from  the  body  that  the  whole  of  the  dose  in  ordinary 
use  is  not  excreted  before  another  is  given,  the  amount  present 
in  the  body  will  gradually  increase,  just  like  the  curare  in  Her- 
mann's experiment,  and  will  produce  an  increasing  or  cumulative 
effect.   Examples  of  this  are  to  be  found  in  metallic  preparations, 

1  Children  absorb  more  quickly  than  adults,  so  opium  is  more  dangerous  to 
them.    Marx,  Lehre  von  den,  Qi/ten,  vol.  ii.p.  117. 


42  PHABMACOLOGY  AND  THEEAPEUTICS.     [sect,  i., 

such  as  those  of  mercury  or  lead,  -which  are  excreted  very  slowly ; 
or  in  some  of  the  organic  alkaloids,  if  given  in  sufficiently  large 
and  frequent  doses.  The  sparingly  soluble  alkaloids  which 
form  stable  compounds  with  the  tissues  and  are  thus  slowly 
eliminated  are  more  liable  to  prove  cumulative.  The  size  of 
the  dose  and  the  frequency  with  which  it  must  be  repeated  in 
order  to  produce  a  cumulative  effect  will  differ  according  to  the 
rapidity  with  which  the  drug  is  excreted ;  for,  if  excretion  be 
rapid,  a  larger  dose  or  more  frequent  repetition  will  be  required. 

Sometimes  the  symptoms  of  the  physiological  action  of  a  drug 
instead  of  increasing  gradually  may  do  so  suddenly,  and  it  is  to 
this  kind  of  action  that  the  term  cumulative  action  is  most, 
usually  applied.  This  may  sometimes  be  due  to  a  sparingly 
soluble  drug  accumulating  in  the  intestinal  canal,  and  being 
suddenly  dissolved  and  absorbed  on  account  of  some  change 
occurring  in  the  intestinal  contents ;  at  other  times  it  may  be  due 
to  arrest  of  excretion,  as  in  the  case  of  the  two  vegetable  active 
principles,  digitalin  and  strychnine,  to  which  an  especial  cumu- 
lative action  is  ascribed.  After  moderate  doses  of  these  drugs 
have  been  taken  for  some  time,  it  is  found  that  instead  of  the 
effects  they  produce  increasing  gradually,  as  we  would  expect' 
from  a  gradual  accumulation  in  the  blood,  the  symptoms  of 
poisoning  become  suddenly  developed,  in  somewhat  the  same 
way  as  if  the  dose  had  been  suddenly  increased.  It  is  evident 
that  a  diminution  in  the  quantity  excreted  will  produce  this 
effect  as  readily  as  an  increase  in  the  quantity  taken,  and  this 
is  probably  the  true  cause  of  the  phenomenon.  "When  digitalin 
has  been  taken  for  some  time  and  accumulated  to  a  certain 
extent  in  the  blood,  it  causes  a  diminution  in  the  amount  of 
urine  excreted,  and  this  diminution  is  either  accompanied  or 
quickly  followed  by  the  other  symptoms  of  poisoning.1  The 
effect,  indeed,  seems  exactly  the  same  as  Hermann  would  have 
obtained  in  his  experiment  if  he  had  only  partially  compressed 
the  renal  arteries  instead  of  ligaturing  them  completely.  For 
digitalin  appears  to  diminish  the  secretion  of  urine  by  causing  a 
powerful  contraction  of  the  renal  vessels,2  and  in  large  doses  may 
completely  arrest  the  secretion  of  urine,3  and  probably  also  the 
circulation  through  the  kidneys.  Strychnine  has  a  similar  action 
on  the  vessels.4 

Effect  of  different  Preparations. — When  a  drug  is  given  in 
a  soluble  form,  and  in  small  bulk,  it  is  more  quickly  absorbed 
and  will  have  greater  effect  than  when  given  in  a  less  soluble 


1  Brunton,  On  Digitalis,  p.  39. 

2  Brunton  and  Power,  Proceedings  of  Royal  Soc,  1874,  No.  153,  and  Central- 
blattf.  d.  Med.  Wiss.,  1874,  p.  497. 

8  Chriatison,  Edin.  Med.  Journ.,  vii.  149. 

*  Grfitzner,  PflUger's  Arohiv,  1876,  Bd.  xi.  p.  601.     Gartner,  Separat-Abdruck 
a.  d.  lxxx.  Bd.  d.  k.  Akad.  d.  Wiss.  III.  Abt.,  Deo.  Heft,  Jahrg.  1879. 


chap,  ii.]    ACTION  OF  DRUGS  ON  THE  ORGANISM.  48 

form  or  much  diluted.  Thus  drugs  given  in  solution  as  tinctures 
will  act,  as  a  rule,  more  quickly  than  when  given  in  the  form  of 
pill  or  powder. 

Effect  of  Fasting. — When  a  drug  is  given  upon  an  empty 
stomach,  it  is  usually  absorbed  much  more  rapidly.  Thus  the 
same  quantity  of  alcohol  which  would  have  no  effect  on  a  man 
if  taken  during  or  after  dinner,  might  intoxicate  him  if  taken 
on 'an  empty  stomach,  and  especially  if  he  were  thirsty,  so  that 
absorption  occurred  rapidly.  Curare,  although  it  is  usually 
inert  when  placed  in  the  stomach,  is  sometimes  absorbed  so 
rapidly  from  an  empty  stomach  as  to  produce  a  certain  amount 
of  paralysis. 

Besides  the  alterations  in  absorption  we  have  to  consider  also 
the  local  action  on  the  stomach  itself,  and  the  reflex  effects  which 
may  be  produced  through  the  gastric  nerves  on  other  organs.  Thus 
where  we  give  a  drug  for  its  local  action  on  the  stomach  itself,  it 
is  administered  with  the  greatest  effect  during  fasting,  as  it  will 
come  in  contact  with  all  parts  of  tbe  gastric  mucous  membrane. 
An  example- of  this  is  the  use  of  a  small  dose  of  arsenic  for 
gastric  neuralgia  or  lientery. 

But  when  we  wish  to  prevent  local  action  on  the  stomach — as, 
for  example,  when  we  give  arsenic  for  its  general  effect  on  the 
system,  in  cases  of  skin-disease — we  administer  it  after  meals,  so 
that  it  may  be  diluted  by  the  food,  and  not  irritate  the  stomach 
too  much. 

Effect  of  Conditions  of  the  Stomach. — In  some  conditions 
of  the  nervous  system,  absorption  takes  place  much  more  slowly 
than  others ;  indeed,  both  digestion  and  absorption  appear  to  be 
sometimes  totally  arrested.  Thus  in  persons  in  whom  a  sick 
headache  comes  on  some  time  after  a  meal  the  contents  of  the 
-stomach  are  vomited  after  a  while  and  the  food  is  found  to  have 
undergone  digestion  but  not  absorption.  If  the  meal  be  taken 
after  the  headache  has  come  on  it  will  be  found,  in  some  persons 
at  least,  that  the  food  is  vomited  almost  unchanged,  both  diges- 
tion and  absorption  appearing  to  be  arrested.  This  condition 
exists  also  in  delirium  tremens,  and  in  a  case  of  this  disease  I 
have  seen  pieces  of  food  thrown  up  in  an  undigested  condition 
although  they  have  been  swallowed,  as  the  patient  has  informed 
me,  three  or  four  days  before.  It  is  probable  that  in  these  con- 
ditions drugs  are  also  not  absorbed,  and  I  think  it  is  not  im- 
probable that  the  harmlessness  of  large  doses  of  digitalis  given 
in  cases  of  delirium  tremens  is  due  to  the  non-absorption  of  the 
drug. 

Effect  of  Habit. — The  tissues  seem  to  have  a  certain  power 
of  adapting  themselves  to  changes  in  their  surroundings.  Thus 
salt-water  amcebaB  will  die  when  placed  at  once  in  fresh  water, 
but  if  the  fresh  water  be  added  very  gradually,  they  may  by-and- 
,by  become  accustomed  to  live  in  it.. .  Fresh-water  amoebae  also 


44  PHAKMACOLOGY  AND  THEEAPEUTICS.     [sect,  u 

have  the  power  of  becoming  gradually  accustomed  to  increasing 
quantities  of  salt  gradually  added  to  the  water  in  which  they 
live,  and  which  would  at  once  kill  them  if  added  suddenly.  A 
similar  power  seems  to  be  possessed  by  the  tissues  of  the  higher 
animals,  in  regard  to  some  drugs  at  least.  Thus  the  arsenic- 
eaters  of  Styria  are  able  to  consume — not  only  without  injury, 
but  with  apparent  benefit  to  themselves — a  quantity  of  arsenic 
Which  would  prove  fatal  to  one  unaccustomed  to  it.  The  same  is 
the  case  wiih  opium  and  morphine.  With  these  latter  drugs  there 
seems  to  be  hardly  any  limit  to  the  quantity  which  can  be  taken 
after  the  habit  has  been  once  established,  and  after  a  certain 
dose  has  been  exceeded. 

It  is  possible,  however,  that  in  addition  to  a  process  of  ac- 
commodation going  on  in  the  tissues,  there  is  a  slower  absorption, 
and  perhaps  more  rapid  excretion,  going  on  at  the  same  time  ; 
for  it  is  observed  in  the  case  of  opium  that  sometimes  the  effect 
is  not  only  diminished,  but  the  time  which  elapses  before  it 
occurs  is  lengthened  when  persons  have  become  accustomed  to 
the  drug. 

In  regard  to  the  possibility  of  very  slow  absorption  we  must 
remember  the  power  of  the  liver  to  arrest  and  excrete  or  to 
destroy  poisons,  especially  as  it  is  chiefly  in  the  case  of  vegetable 
poisons  that  their  power  is  lessened  by  habit,  which  has  much 
less  influence  on  the  effect  of  inorganic  substances.  The  toler- 
ance of  some  inorganic  drugs,  and  especially  of  tartar  emetic  in 
disease  or  after  repeated  doses,  may  be  due  to  fever  or  the 
drug  itself  lessening  the  acidity  of  the  stomach,  and  consequently 
the  action  of  the  drug,  which  acts  most  strongly  in  presence  of 
an  acid. 

The  Effect  of  Temperature. — Chemical  reactions,  as  a  rule, 
go  on  more  rapidly  the  higher  the  temperature,  excepting  when 
very  high  temperatures  are  reached  and  dissociation  occurs. 
The  effect  of  drugs  upon  living  organisms  may  be  regarded  as 
being  to  a  great  extent  due  to  chemical  union  between  the  drugs 
and  the  organism,  and  therefore  we  should  expect  that  alterations 
in  temperature  would  greatly  affect  the  action  of  drugs  and  that, 
as  a  rule,  we  should  find  that  they  would  act  with  greater  quick- 
ness when  the  temperature  is  high  unless  some  other  factor 
should  be  brought  into  operation  by  the  increasing  temperature. 
Experience  confirms  this  expectation,  and,  as  a  matter  of  fact, 
the  effect  of  temperature  on  the  action  of  drugs  is  very  great. 
At  different  temperatures  the  administration  of  the  same  drug 
may  be  followed  by  different  results,  and  it  is  probable  that  a 
great  number  of  the  contradictory  observations  which  we  find 
in  works  on  Pharmacology  are  due  to  this  most  important  factor 
having  been  neglected  in  making  the  experiments.  It  is  of  the 
greatest  importance  to  the  physician  also,  as  many  of  the  cases 
of  disease  which  he  has  to  treat  are  accompanied  by  a  rise  in 


chap,  ii.]    ACTION  OF  DRtJGS  ON  THE  ORGANISM.  45 

temperature  which  may  have  a  very  important  effect  upon  the 
action  of  the  drugs  which  he  administers. 

•  The  alteration  produced  in  the  effect  of  drugs  by  warmth,  was 
first  noticed  by  Alexander  von  Humboldt,  who  observed  that 
warmth  not  only  acted  as  a  stimulant  to  the  heart  in  increas- 
ing the  power  and  rapidity  of  its  contractions,  but  noticed  that 
warmth  increased  the  rapidity  with  which  alcohol  destroyed  the 
irritability  of  a  nerve,  and  potassium  sulphide  that  of  a  muscle. 
Bernard  observes  generally  that  poisons  act  slightly  on  frogs 
.when  cooled  down,  and  become  more  active  the  higher  the  tem- 
perature. The  effect  of  warmth  in  stimulating  the  movements 
of  protoplasmic  structures,  such  as  amoebae  and  cilia,  was  in- 
vestigated by  Kiihne ;  and,  in  an  important  research,  Luchsinger 
experimented  on  the  influence  of  warmth  on  the  action  of  poisons 
on  many  organs,  and  found  that  the  ciliary  motion  in  the 
pharynx  of  the  frog  became  paralysed  by  chloral,  potassium 
carbonate,  and  tartrate  of  copper  and  sodium  more  and  more 
quickly  in  proportion  to  the  rise  in  temperature.  On  cooling 
down  the  ciliary  movement  again  returned. 

Dr.  Cash  and  I  have  found  that  the  action  of  veratrine  or 
barium  on  muscle  is  very  much  altered  by  heat  and  cold.  At 
ordinary  temperatures  contraction  is  greatly  prolonged,  but  under 
the  influence  of  either  great  heat  or  great  cold  the  contraction 
again  becomes  nearly  or  quite  normal. 

Many,  if  not  all,  muscular  poisons  act  more  quickly  with 
increased  temperature ;  and  frogs  poisoned  with  chloral,  copper, 
manganese,  potash,  and  zinc  are  paralysed  more  quickly  when 
the  temperature  is  high,  than  when  it  is  low,  whether  the  alter- 
ations be  produced  artificially,  or  be  due  to  differences  in  the 
season  at  which  the  experiments  are  made. 

Eabbits  poisoned  with  copper  or  potash  also  die  more  quickly 
when  placed  in  a  warm  chamber  than  when  left  at  the  ordinary 
temperature. 

The  terminations  of  motor  nerves  in  the  muscles  are  also 
greatly  affected  by  temperature. 

Guanidine  produces  in  the  frog  fibrillary  twitchings  of  the 
muscles,  which  persist  even  in  excised  muscles,  but  are  removed 
by  curare,  and  are  therefore  in  all  probability  dependent  on  an 
affection  of  the  terminal  ends  of  the  motor  nerves  in  the  muscle. 
Luchsinger  found  that  when  four  frogs  are  poisoned  in  this 
way,  and  one  is  placed  in  ice- water,  another  in  water  at  18°,  a 
third  at  25°,  and  a  fourth  at  32°,  the  fibrillary  twitchings  soon 
disappear  from  the  muscles  of  the  frog  at  0°,  and  only  return 
when  its  temperature  is  raised  to  about  18°.  In  the  one  at  18° 
convulsions  occur,  which  are  still  greater  in  the  one  at  25°.  In 
the  frog  at  32°,  on  the  other  hand,  no  abnormal  appearance  is 
to  be  remarked,  and  five  times  the  dose  may  be  given  without 
doing  it  any  harm. 


46  .PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  V 

This  poison  then  resembles  veratrine  in  acting  only  at  ordi- 
nary temperatures,  and  in  its  action  being  abolished  by  excess  of 
heat  or  cold. 

The  effect  of  temperature  on  secreting  nerves  is  well  marked. 
When  the  sciatic  is  stimulated  in  an  animal,  the  corresponding 
foot  usually  begins  to  sweat,  but  the  sweating  is  very  much  less 
if  the  foot  is  cooled  down  than  if  it  is  warm.  A  similar  action 
is  exerted  by  temperature  upon  the  sweating  produced  by  pilo- 
carpine— a  drug  which  appears  to  act  by  stimulating  the  ends 
of  the  secreting  nerves.  When  the  animal  is  cooled,  this  drug 
is  much  less  powerful  than  when  it  is  warm. 

Overheating  appears  to  have  an  opposite  action,  and  when 
the  foot  is  heated  up  to  a  certain  temperature  it  does  not  secrete 
nearly  so  readily,  even  though  the  glands  themselves  are  not  in- 
jured, and  secretion  may  commence  after  the  lapse  of  a  little  time. 

The  influence  of  poisons  on  the  heart  of  the  frog  is  also 
modified  by  temperature.  Kronecker  found  that  its  beats  were . 
arrested  by  ether  easily  and  quickly  when  the  temperature  was 
high,  but  with  great  difficulty  when  it  was  low.  Kinger  found 
that  a  small  dose  of  veratrine  greatly  affects  the  ventricle  at  a 
moderate  or  high  temperature,  but  at  a  low  temperature  produces 
no  effect.1 

Luchsinger  noticed  that  when  the  frog's  heart  had  been 
arrested  by  passing  dilute  solutions  of  chloral,  copper,  or  potas- 
sium carbonate  through  at  25°  C,  the  pulsations  again  began 
when  the  temperature  was  reduced  to  15°  C.  When,  on  the 
contrary,  the  heart  had  been  arrested  in  a  similar  manner,  at  a 
temperature  of  5°  C,  pulsations  could  then  be  induced  by  warm- 
ing it  to  15°. 

Some  extraordinary  observations  on  the  effect  of  temperature 
upon  the  action  of  drugs  on  the  spinal  cord  have  been  made  by 
Kunde  and  Poster,  who  have  found  that,  in  a  number  of  frogs 
poisoned  with  strychnine  and  exposed  to  different  temperatures, 
raising  the  temperature  diminishes  the  convulsions,  while  cold 
increases  them  if  small  doses  are  employed.  Baising  the  tem- 
perature, indeed,  may  not  only  diminish  but  entirely  abolish  the 
convulsions,  while  putting  a  frog  in  ice  may  bring  them  on  when 
they  would  not  otherwise  appear,  and  cause  them  to  last  for  no 
less  than  twenty-four  hours.  When  large  doses  are  employed 
the  opposite  effect  is  produced;  raising  the  temperature  then 
increases  the  convulsions,  while  cooling  the  frog  down  to  0° 
abolishes  them. 

An  observation  similar  in  some  respects,  though  differing  in 
others,  has  been  made  on  the  effect  of  temperature  on  the  action 
of  picrotoxin  by  Luchsinger.2   When  this  poison  is  given  to  three 


1  Ringer,  Archives  of  Medicine,  vol.  vii.  Feb.  1882,  p.  5. 
!  Luchsinger,  Physiologische  Studien,  Leipzig,  18S2. 


chap,  ii.]    ACTION  OF  DEUGS  ON  THE  OEGANISM.  47 

frogs,  and  they  are  then  placed  in  water  at  0°,  15°,  and  32°, 
in  a  few  minutes  the  convulsions  occur  in  the  one  at  32°,  shortly 
afterwards  in  that  at  15°,  while  the  one  at  0°  remains  for  a  long 
time  completely  unaffected,  and  only  exhibits  signs  of  convulsion 
when  the  dose  has  been  very  great  indeed,  or  when  it  is  taken 
out  of  the  cold  bath. 

The  effect  of  warmth  in  accelerating  death  from  muscular 
poisons  has  already  been  mentioned. 

The  power  of  warmth  to  preserve  life  in  narcotic  poisoning 
was  observed  by  Hermann  in  relation  to  alcohol,  which  rabbits 
bear  better  when  they  are  somewhat  warmed.1  Its  extraordinary 
effect  in  preventing  death  in  animals  poisoned  with  chloral  was 
noticed  by  Strieker,  and  more  thoroughly  worked  out  by  myself 
at  his  suggestion.2  Death  by  chloral  appeared  from  my  ex- 
periments to  be  in  a  great  measure  due  to  continued  loss  of  heat 
from  the  animal.  This  seems  to  be  the  case  also  in  metallic 
poisoning  by  copper,  manganese,  mercury,  platinum,  potassium, 
thallium,  tungsten,  and  zinc.  Its  cause  appears  to  be  twofold : 
(1)  the  poisons  lessen  combustion  in  the  body,  and  the  amount 
of  heat  produced,  as  is  shown  by  their  diminishing  the  amount 
of  carbonic  acid  excreted ;  (2)  besides  disturbing  the  production 
they  also  disturb  the  regulation  of  heat,  so  that  animals  poisoned 
by  them  have  less  power  of  resisting  the  influence  of  external 
temperature,  and  therefore  the  temperature  rises  more  quickly 
when  they  are  put  in  a  warm  chamber,  as  well  as  sinks  more 
quickly  when  they  are  exposed  to  cold. 

All  these  observations  show  that  the  definition  of  the  action 
of  a  drug,  already  given  (p.  5),  must  be  still  further  modified, 
and  we  must  define  it  as  the  reaction  between  the  drug  and  the 
various  parts  of  the  body  at  a  certain  temperature. 

Thomas 3  found  that  digitalis  has  sometimes  no  action  on  the 
pulse  in  pneumonia.  As  the  slowing  of  the  pulse  produced  by 
this  drug  is  to  some  extent  effected  through  the  vagi,  it  occurred 
to  me  that  its  want  of  action  in  this  disease  might  be  due  to  the 
paralysis  of  these  nerves  by  heat.  On  testing  the  action  of  heat, 
however,  on  the  vagus,  in  rabbits  deeply  chloralised,  I  found  that 
it  was  not  paralysed  at  a  temperature  just  sufficient  to  kill  the 
animal.4  Cash  and  I,  however,  have  found  that  though  the 
peripheral  ends  of  the  vagi  are  not  completely  paralysed  by  high 
temperature,  the  roots  of  the  vagus  in  the  medulla  appear  to  be  • 
so,  and  probably  the  want  of  action  of  digitalis,  when  the  tem- 
perature is  high,  is  due  to  this  paralysis  {vide  Digitalis). 

The  abnormal  effect  which  opium  has  in  some  cases  of  fever 
— causing  excitement   instead   of    sleep — is  occasionally  most 

1  Hermann,  Arch.f.  Anat.  u.  Physiol.  1867,  p.  64. 

"  Lauder  Brunton,  Journal  of  Anatomy  and  Physiology,  vol.  viii. 

•  Arch.f.  Heilk.,  vol.  iv.  329,  1865. 

*  St.  Bartholomew's  Hospital  Reports,  1871,  p.  216. 


48  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect,  u 

distressing  to  the  physician.  It  is  possible  that  this  may  be 
partly  due  to  the  temperature,  and  that  the  combination  of 
tartar  emetic  with  the  opium  may  owe  some  of  its  utility  to  its 
effect  in  lowering  temperature,  although  not  improbably  both  it 
and  another  useful  combination  with  chloral  also  act  more  per- 
fectly on  account  of  the  depressing  action  on  the  circulation. 
These  are  points,  however,  on  which  further  observations  are 
greatly  needed. 

Climate. — It  is  said  that  the  action  of  narcotic  drugs  is 
greater  in  warm  climates  than  in  cold,  and  that  smaller  doses 
are  therefore  required  to  produce  a  similar  effect.  If  this  state- 
ment be  true,  it  may  be  due  to  the  higher  temperature,  for 
Crombie  has  shown  that  in  India  the  average  temperature  of  the 
body  is  about  half  a  degree  higher  than  in  England.  It  may, 
however,  be  due  to  the  slower  elimination  of  the  drug  by  the 
urine ;  because  in  hot  climates  the  secretion  of  the  skin  is  apt 
to  be  much  greater,  and  the  secretion  of  urine  and  elimination 
by  it  consequently  less. 

Time  of  Day. — In  healthy  persons  fluctuations  of  the  body- 
temperature  occur.  The  lowest  temperatures  occur  at  night 
between  10  p.m.  and  1  a.m.,  and  in  the  early  morning  between 
6  and  8  a.m.  The  highest  temperature  occurs  between  4  and  5 
in  the  afternoon. 

The  action  of  drugs  may  be  partially  altered  by  the  slight 
variations  in  temperature  which  occur  within  the  body,  and 
perhaps  still  more  by  the  variations  in  tissue-change,  of  which 
these  fluctuations  of  temperature  are  the  indication.  Thus  tbe 
necessity  for  great  attention  to  the  administration  of  stimulants 
in  the  early  hours  of  the  morning  in  cases  of  threatening  collapse 
has  long  been  recognised. 

Effect  of  Season. — The  action  of  drugs  is  altered  by  the 
changes  in  temperature  due  to  the  seasons.  Galen  supposed 
that-  the  quantity  of  blood  in  the  body  was  increased  in  spring, 
and  in  this  country,  till  within  recent  years,  it  was  a  common 
custom  for  people  to  be  regularly  bled  every  spring.  Purgatives 
were  not  unfrequently  administered  also  at  the  same  time. 
There  are,  no  doubt,  changes  corresponding  with  the  seasons  in 
the  human  organisation,  although  these  are  better  marked  in 
the  lower  animals ;  e.g.  deer,  in  which  the  antlers  bud  regularly 
in  spring  and  reach  perfection  just  at  the  breeding  season.  It  is 
possible  that  the  abolition  of  the  practice  of  bleeding  in  spring 
and  the  changes  in  other  plans  .of  treatment  formerly  adopted, 
may  not  be  altogether  due,  as  some  suppose,  to  increased  know- 
ledge on  our  part,  but  rather  to  the  occurrence  of  a  change  of 
type  not  only  in  diseases  but  also  in  slight  ailments,  and  to  the 
need  for  such  treatment  having  disappeared.  Formerly,  before 
the  introduction  of  coaches,  and  still  more  of  railways,  locomotion 
was  difficult  and  transportation  was  expensive ;   in  consequence 


chap,  ii.]    ACTION  OF  DRUGS  ON  THE  ORGANISM.  49 

of  this,  the  food  consumed  by  the  generality  of  people  was  differ- 
ent in  character,  loaf  bread  being  very  little  used,  and  salt  meat 
often  used  for  weeks  and  months  together  during  the  winter, 
with  comparatively  few  vegetables.  Such  a  diet  might  naturally 
lead  to  a  condition  of  body  which  would  be  benefited  by  bleeding 
and  purgatives. 

Effect  of  Disease. — The  direct  and  indirect,  the  local  and 
remote  action  of  drugs  upon  the  complicated  mechanism  of  a 
mammalian  body  is  so  perplexing  that  the  attempt  to  ascertain 
the  precise  mode  of  action  of  a  drug  by  its  mere  administration, 
either  to  a  healthy  man  or  to  healthy  animals,  and  observation 
of  its  effect  upon  them,  is  hopeless. 

Moreover,  the  object  that  we  really  wish  to  attain  is  the 
power  to  relieve  human  suffering,  and  to  avert  the  premature 
death  due  to  disease.  But  in  disease  we  have  new  factors; 
changes  are  produced  by  it  in  the  functions  of  the  body,  and 
the  reaction  of  the  diseased  organism  to  the  drugs  which  we  ad- 
minister is  oftentimes  different  from  that  of  a  healthy  one.  To  a 
man  suffering  from  cholera,  for  example,  enormous  doses  of  drugs 
have  been  given  without  the  least  effect ;  and,  in  the  wakefulness 
of  fever,  the  opium  which  ought  to  produce  sleep  may  simply 
cause  excitement  and  delirium. 


Use  of  Experiments. 

As  we  have  seen,  the  problems  put  before  us  are  too  com- 
plicated to  be  solved  directly,  and  we  must  therefore  simplify 
them. 

This  is  done  in  four  ways : — 

1st,  by  observation  of  the  effects  of  drugs  on  animals  with 
a  simpler  organism  than  our  own,  such  as  amoebae 
or  frogs ; 

2ndly,  by  applying  the  drug  to  some  part  of  an  animal 
body  more  or  less  completely  separated  from  the  rest, 
such  as,  for  example,  the  muscle  and  nerve,  or  the 
heart  of  a  frog  separated  from  the  body ;  and 

3rdly,  by  preventing  the  drug  from  reaching  one  part  of 
the  body  while  it  acts  on  the  others,  as  by  ligaturing 
an  artery,  as  in  Bernard's  or  Kolliker's  experiments  on 
curare. 

4thly,  by  producing  artificial  changes  in  the  relations  of 
the  various  parts  of  the  body  of  higher  animals, 
either  before  or  after  administration  of  a  drug,  as, 
for  example,  by  dividing  the  vagi,  in  order  to  ascer- 
tain how  far  the  change  produced  in  the  beats  of  the 
heart  by  a  drug  is  due  to  its  action  upon  it  through 
these  nerves. 


50  PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

Comparative  Pharmacology. — It  may  seem  almost  absurd 
to  those  unacquainted  with  the  subject,  that  so  much  attention 
should  be  devoted  to  experiments  on  the  effect  of  drugs  on  the 
lower  animals,  when  our  object  is,  as  we  have  just  stated,  to 
ascertain  their  action  upon  human  beings,  and  their  mode  of 
employment  in  the  diseases,  of  man. 

But  in  the  study  of  Pharmacology,  just  as  in  Histology,  very 
much  is  to  be  learned  by  comparative  studies.  In  his  lectures, 
Ranvier  admirably  defines  General  Anatomy  as  Comparative 
Histology  limited  to  a  single  organism.  He  illustrates  this  by 
showing  that  the  different  modes  of  movement  which  occur  in 
some  of  the  lower  classes  of  the  animal  kingdom  are  to  be  found 
united  in  the  highest.  Thus  leucocytes  of  the  blood  move  about 
like  amoebae.  The  epithelium  of  the  respiratory  passages  is  pro- 
vided, like  infusoria,  with  cilia ;  and  while  some  muscles  have  the 
power  of  rapid  contraction,  others  contract  slowly,  like  those  of 
some  invertebrata.1 

We  have  thus  in  certain  parts  of  the  bodies  of  the  higher 
animals  and  of  man,  anatomical  elements  whose  functions  are 
performed  in  a  way  resembling  that  of  organisms  low  in  the 
scale  of  existence,  and  by  examining  the  effects  of  drugs  upon 
these  low  organisms  we  acquire  knowledge  which  aids  us  in  deter- 
mining the  action  of  drugs  upon  similar  anatomical  elements  in 
the  human  body. 

In  his  admirable  lecture  on  Elemental  Pathology,  Sir  James 
Paget  draws  attention  to  the  distinction  between  the  conditions 
of  life  and  the  essential  properties  of  living  things ;  and  to  the 
fact  that,  while  the  various  parts  of  a  complicated  organism  like 
the  human  body  are  closely  connected  together,  and  made  to 
work  in  harmony  for  the  common  good  of  the  organism  in 
health,  yet  each  part  retains  its  own  mode  of  life,  and  may 
sometimes  develop  to  an  excessive  extent  at  the  expense  of  the 
rest,  and  may  destroy  the  organism,  and  itself  as  well.  We  see 
the  power  which  each  part  possesses  of  carrying  on  individual 
life  apart  from  the  rest  best  in  lower  organisms  or  in  inorganic 
substances,  where  the  parts  are  less  dependent  on  the  welfare  of 
the  whole. 

Thus,  in  crystals,  a  chip  which  has  been  broken  off  is  re- 
placed, and  the  form  of  the  crystal  restored,  by  putting  it  in  a 
solution  which  will  yield  it  the  proper  kind  of  material  required. 
When  a  hydra  is  cut  in  two,  each  part  grows  into  a  perfect  in- 
dividual :  a  tail  growing  to  the  head  part,  and  a  head  growing 
to  the  tail  part.  When  a  claw  has  been  broken  off  a  crab  or 
lobster,  a  new  one  will  by-and-by  grow ;  but  if  the  animal  be 
divided  in  two,  unlike  the  hydra  it  will  die. 


1  Legons  d'anatomie  ginirale  sur  le  systime  musculaire,  par  L.  Ranvier     Paris, 
18S0,  p.  46. 


ceap.  ii.]    ACTION  OF  DEUGS  ON  THE  OBGANISM.  51 

As  we  ascend  in  the  scale  of  existence  the  power  of  repair 
becomes  less  perfect.  But  even  in  the  human  being  we  see  that 
the  different  parts  retain  their  individual  life,  and  if  put  into 
proper  conditions  may  live,  although  the  original  body  from 
which  they  were  obtained  were  to  die.  Teeth,  for  example, 
which  have  been  extracted  from  one  person  have  been  trans- 
planted and  grown  in  the  jaws  of  another ;  and  the  transplanta- 
tion of  hair,  skin,  or  of  periosteum  is  perfectly  practicable. 

Idiosyncrasy. — -In  then-  onward  development  from  the 
lowest  forms  of  life,  man  and  the  higher  animals  have  not 
only  permanently  retained  in  their  bodies  certain  parts  which 
resemble  organisms  low  in  the  scale  of  existence,  but  every 
now  and  again  a  tendency  to  reversion  appears  in  certain 
individuals,  and  we  thus  get  anatomical  abnormalities  and 
malformations. 

These  were  formerly  inexplicable,  but  the  doctrine  of  evolution 
has  thrown  much  light  on  their  probable  causation. 

Now  and  again  we  also  meet  with  peculiarities  in  the  re- 
action between  drugs  and  parts  of  the  human  body  in  certain 
individuals. 

Some  persons,  for  example,  are  like  pigeons — only  slightly 
affected  by  opium — and  can  take  enormous  doses  of  it  without 
any  apparent  effect.  Others,  again,  are  peculiarly  sensitive  to 
the  action  of  certain  medicines,  and  a  dose  of  a  mercurial 
preparation,  which  would  have  but  a  slight  purgative  action  on 
one,  will  produce  intense  salivation  in  another. 

These  personal  peculiarities  in  regard  to  the  action  of  drugs, 
or  idiosyncrasies,  as  they  are  termed,  have  been,  _  and  are  still, 
very  perplexing  td  the  medical  practitioner.  It  is  probable,  how- 
ever, that  a  more  complete  study  of  comparative  pharmacology 
will  enable  us,  to  some  extent  at  least,  to  recognise  these,  and 
thus  to  avoid  the  inconvenience  which  they  occasion. 

Experiments  upon  Healthy  Man. — As  the  action  of  drugs 
upon  animals  is  to  a  certain  extent  different  from  that  on  man, 
it  is  undoubtedly  desirable  to  ascertain  the  action  of  drugs  by 
experiments  upon  healthy  man.  This  is  all  the  more  necessary 
because  by  experiments  upon  animals  we  are  able  to  discover 
only  the  ruder  differences  between  drugs,  and  we  cannot  ascer; 
tain  the  finer  shades  of  action,  both  because  it  is  in  man  alone 
that  these  finer  differences  occur,  and  because  it  is  he  alone  who 
can  give  information  regarding  slight  changes  which  he  can  per- 
ceive in  his  own  organism,  but  which  are  imperceptible  to  others 
who  may  be  observing  him.  There  is  no  doubt  that  many  ob- 
servers of  this  sort,  several  of  whom  have  been  homceopathists, 
have  done  good  service  to  medicine  by  carefully  noting  and  care- 
fully comparing  the  symptoms  produced  by  various  drugs.  These 
observations,  however,  are  liable  to  fallacies,  as  I  will  presently 
mention. 

E  2 


52  PHARMACOLOGY   AND   THERAPEUTICS,      [sect.  i. 

Fallacies  of  Experiment  upon  Man.— But  the  high  de- 
velopment of  the  nervous  system  in  man,  its  susceptibility  to 
various  influences,  and  the  power  of  expression  which  man 
possesses— the  very  qualities  which  render  him  such  a  valuable 
subject  for  experiment  make  experiments  upon  him  all  the  more 
liable  to  fallacy.  Thus  we  find  that  in  the  experiments  of  Hein- 
rich  and  Dworzak  aconite  was  found  to  cause  neuralgic  pains 
in  the  face ;  but  unfortunately  these  observers  have  not  mentioned 
whether  any  carious  teeth  were  present,  and  so  we  cannot  ascer- 
tain whether  the  neuralgia  was  due  to  the  action  of  the  aconite 
itself  upon  healthy  nerves,  or  to  alterations  in  the  circulation  of 
the  alveoli  lodging  decayed  teeth. 

One  of  the  most  marked  examples  of  the  fallacies  occurring 
in  experiments  upon  man,  and  of  the  errors  to  which  such 
fallacies  may  lead,  is  to  be  found  in  the  provings  which  Hahne- 
mann made  of  cinchona  bark,  and  which  led  him  to  formulate 
the  doctrine  of  homoeopathy.  Hahnemann,  who  had  suffered 
from  ague,1  for  the  sake  of  experiment,  took  for  several  days 
4  drachms  of  good  cinchona  bark  twice  a  day,  and  then  began  to 
suffer  from  all  the  ordinary  symptoms  of  intermittent  fever.  On 
leaving  off  the  drug  he  soon  became  quite  well.  He  therefore 
concluded  that  cinchona  bark,  which  was  well  known  to  be  a 
remedy  for  ague,  could  also  produce  it. 

Everyone  who  has  an  extended  experience  of  ague  knows 
well  that  even  when  patients  have  been  free  from  any  symptoms 
of  the  disease  for  a  considerable  length  of  time,  they  may  be 
caused  to  reappear  by  various  conditions,  and  more  especially  by 
anything  that  irritates  the  stomach  or  intestines.  I  have  not 
myself  seen  a  case  of  ague  brought  on  by  the'  administration  of 
cinchona  bark,  but  I  have  seen  it  occur  after  a  succession  of 
heavy  dinners  in  a  patient  who  had  been  long  free  from  it. 
Powdered  cinchona  is  certainly  irritant,  and  Jorg  found  that 
in  two-drachm  doses  it  might  cause  flatulence,  irritation,  and 
nausea.  Hahnemann  took  it  in  double  this  dose,  and  in  all 
probability  the  ague  which  it  brought  on  was  simply  due  to 
gastric  irritation,  and  not  to  any  specific  action  of  the  cinchona. 
Had  Hahnemann  taken  any  other  irritant  which  disagreed  with 
him — say  tartar  emetic,  or  perhaps  even  pork-pie — he  might 
have  suffered  in  the  same  way,  and  yet  pork-pie  could  hardly  be 
said  to  be  a  specific  for  ague. 

Experiments  in  Disease. — In  the  present  state  of  medicine 
every  attempt  which  we  make  to  treat  disease  by  the  administra- 
tion of  medicine  partakes  more  or  less  of  the  nature  of  experi- 
ment, because  we  can  rarely  be  absolutely  certain  that  the  drug 


1  History  of  Homccopathy.  By  Wilhelm  Ameke,  M.D.  Translated  by  Alfred  E. 
Drysdale,  M.B.  Edited  by  B.  E.  Dudgeon,  M.D.  London.  Published  for  the 
British  Homeopathic  Society,  by  E.  Gould  &  Son,  59  Moorgate  Street.     1S85 


chap,  n.]    ACTION  OP  DBUGS  ON  THE  ORGANISM.  53 

will  have  precisely  the  effect  which  we  desire.  As  the  phrase  is, 
'We  try  one  medicine,  and  then  we  try  another.'  If  human 
life  were  not  so  valuable,  we  might  pursue  a  series  of  systematic 
experiments,  and  gain  valuable  information  ;  but  it  is  impossible 
for  a  physician  to  treat  the  patient  who  calls  upon  him  for  aid  in 
any  other  way  than  that  which  seems  likely  to  be  the  best  for 
the  patient's  welfare.  Here  again  the  homceopathists  have  done 
good  service,  because  by  administering  to  the  patient  medicines 
in  which  they  believed,  but  which  could  neither  do  good  nor 
harm,  they  have  taught  us  the  natural  course  of  some  diseases, 
which  we  could  not  otherwise  have  learned. 

Objections  to  Experiment. — Some  people  object  entirely 
to  experiments  upon  animals.  They  do  this  chiefly  on  two 
grounds.  The  first  is  that  such  experiments  are  useless,  and 
the  second  is  that,  even  if  they  were  useful,  we  have  no  right  to 
inflict  pain  upon  animals. 

The  first  objection  is  due  to  ignorance.  Almost  all  our  exact 
knowledge  of  the  action  of  drugs  on  the  various  organs  of  the 
body,  as  well  as  the  physiological  functions  of  these  organisms 
themselves,  has  been  obtained  by  experiments  on  animals. 

The  second  objection  is  one  which,  if  pushed  to  its  utmost 
limits  and  steadily  carried  out,  would  soon  drive  man  off  the  face 
of  the  earth. 

The  struggle  for  existence  is  constantly  going  on,  not  only 
between  man  and  man,  but  between  man,  the  lower  animals  and 
plants,  and  man's  very  being  depends  upon  his  success. 

We  kill  animals  for  food.  We  destroy  them  when  they  are 
dangerous  like  the  tiger  or  cobra,  or  destructive  like  the  rat  or 
mouse.  We  oblige  them  to  work  for  us,  for  no  reward  but  their- 
food ;  and  we  urge  them  on  by  whip  and  spur  when  they  are 
unwilling  or  flag.  No  one  would  think  of  blaming  the  messenger 
who  should  apply  whip  and  spur  to  bring  a  reprieve,  and  thus 
save  the  life  of  a  human  being  about  to  die  on  the  scaffold,  even 
although  his  horse  should  die  under  him  at  the  end  of  the 
journey.  Humane  people  will  give  an  extra  shilling  to  a  cab- 
man in  order  that  they  may  catch  the  train  which  will  take  them 
to  soothe  the  dying  moments  of  a  friend,  without  regarding  the 
consequences  to  the  cab-horse.  Yet  if  one-tenth  of  the  suffering 
which  the  horse  has  to  endure  in  either  of  the  cases  just  men- 
tioned were  to  be  inflicted  by  a  physiologist  in  order  to  obtain 
the  knowledge  which  would  help  to  relieve  the  suffering  and 
lengthen  the  life,  not  of  one  human  being  only,  but  of  thousands, 
many  persons  would  exclaim  against  him.  Such  objections  as . 
these  are  due  either  to  want  of  knowledge  or  want  of  thought  on 
the  part  of  the  people  who  make  them.  They  either  do  not  know 
the  benefits  which  medicine  derives  from  experiment,  or  they 
thoughtlessly  (sometimes,  perhaps,  wilfully)  ignore  the  evidence 
regarding  the  utility  of  experiment. 


54:  PHAEMACOLOGY  AND   THEEAPEUTICS.      [sect.  i. 

One  of  the  most  important  objections  that  has  been  raised  to 
this  mode  of  experiment  is  that  the  action  of  drugs  on  the' lower 
animals  is  quite  different  from  their  action  on  man.  This 
objection  has  a  certain  amount  of  truth,  but  is  in  the  main 
groundless.  The  action  of  drugs  on  man  differs  from  that  on  the 
lower  animals  chiefly  in  respect  to  the  brain,  which  is  so  much 
more  greatly  developed  in  man. 

Where  the  structure  of  an  organ  or  tissue  is  nearly  the  same 
in  man  and  in  the  lower  animals,  the  action  of  drugs  upon  it  is 
similar.  Thus  we  find  that  carbonic  oxide  and  nitrites  produce 
similar  changes  in  the  blood  of  frogs,  dogs,  and  man,  that  curare 
paralyses  the  motor  nerves  alike  in  them  all,  and  veratrine  exerts 
upon  the  muscles  of  each  its  peculiar  stimulant  and  paralysing 
action. 

Where  differences  exist  in  the  structure  of  the  various  organs, 
we  find,  as  we  would  naturally  expect,  differences  in  their  re- 
action to  drugs.  Thus  the  heart  of  the  frog  is  simpler  than  that 
of  dogs  or  men,  and  less  affected  by  the  central  nervous  system. 
We  consequently  find  that  while  such  a  drug  as  digitalis  has 
a  somewhat  similar  action  upon  the  hearts  of  frogs,  dogs,  and 
men,  there  are  certain  differences  between  its  effect  upon  the 
heart  of  a  frog  and  that  of  mammals.  In  all  it  seems  to  affect 
the  muscular  substance  and  cause  increased  contraction.  But 
while  the  frog  almost  invariably  dies  with  the  heart  in  a  state  of 
tetanic  contraction,  this  is  not  the  case  with  dogs  or  men,  where 
the  heart  sometimes  is  found  in  diastole  after  death. 

Ipecacuanha  or  tartar  emetic  will  cause  vomiting  in  man,  but 
does  not  do  so  in  rabbits.  The  reason  of  this  is  that  the  position 
of  the  stomach  in  the  rabbit  is  different  from  that  in  man,  and 
is  such  that  the  animal  cannot  vomit.  In  dogs,  however,  the 
position  of  the  stomach  agrees  with  that  of  man,  and  tartar 
emetic  or  ipecacuanha  causes  vomiting  in  both.  Belladonna 
offers  another  example  of  apparent  difference  in  action — a  con- 
siderable dose  of  belladonna  will  produce  almost  no  apparent 
effect  upon  a  rabbit,  while  a  smaller  dose  in  a  dog  or  a  man 
would  cause  the  rapidity  of  the  pulse  to  be  nearly  doubled.  Yet 
in  all  three — rabbits,  dogs,  and  men — belladonna  paralyses  the 
power  of  the  vagus  over  the  heart.  The  difference  is,  that  in 
rabbits  the  vagus  normally  exerts  but  little  action  on  the  heart, 
and  the  effect  of  its  paralysis  is  consequently  slight  or  hardly 
appreciable,  the  pulse  being  normally  almost  as  quick  as  it  is 
after  the  vagus  is  paralysed.  In  dogs  and  men,  on  the  contrary, 
the  vagus  is  constantly  exerting  considerable  restraining  power 
over  the  heart,  and  the  effects  of  its  paralysis  at  once  attract 
attention. 

An  example  of  the  apparent  difference  in  the  effect  of  a  drug 
on  different  animals  is  afforded  by  nitrite  of  amyl.  If  we  measure 
the  pressure  of  the  blood  in  the  arteries  of  a  rabbit  and  of  a  dog. 


chap,  ii.]    ACTION  OF  DEUGS  ON  THE  OKGANISM.  55 

and  then  cause  them  to  inhale  nitrite  of  amyl,  we  find  that  the 
small  vessels  have  become  widened  and  allow  the  blood  to  pass 
easily  out  of  the  arterial  system  into  the  veins,  so  that  the 
pressure  sinks  considerably  in  the  rabbit,  whereas  it  sinks  only 
slightly  in  the  dog.  The  action  seems  at  first  sight  different ; 
but  when  we  examine  it  more  closely,  we  find  that  the  heart  of 
the  dog  is  no  longer  beating  slowly,  but  very  quickly,  so  as  to 
keep  up  the  pressure,  notwithstanding  the  rapid  flow  of  the 
blood  through  the  widened  vessels,  while  the  heart  of  the  rabbit 
was  going  so  fast  before  that  it  could  not  go  much  more  quickly. 
If  we  cut  the  vagi  in  the  dog,  so  that  the  heart  goes  as  quickly 
as  in  the  rabbit  before  it  begins  to  inhale,  the  blood-pressure 
sinks  during  the  inhalation,  just  as  it  does  in  the  rabbit.1 

One  of  the  most  marked  differences  between  the  action  of  a 
drug  upon  lower  animals  and  upon  man  is  to  be  found  in  the 
effect  of  morphine  upon  frogs  and  upon  pigeons.  In  frogs  it 
causes  convulsions ;  on  pigeons,  even  in  large  doses,  it  produces 
no  apparent  effect.  But  although  its  effects  are  not  appreciable 
to  the  eye,  they  exist  nevertheless,  and  on  applying  the  thermo- 
meter it  is  found  that  morphine  lowers  the  temperature  of  pigeons 
many  degrees.  On  comparing  the  effect  of  the  drug  on  frogs 
with  its  effect  on  man,  we  see  that  in  the  frog  the  cerebral  hemi- 
spheres are  very  slightly  developed  indeed  as  compared  with 
man,  and  in  the  latter  the  effects  of  the  drug  upon  the  spinal 
cord  are  usually  completely  concealed  by  the  narcotic  effect  of 
the  drug  upon  the  brain.  In  children,  however,  and  in  some 
races  of  man  where  the  cerebral  hemispheres  are  less  developed 
than  in  Europeans,  the  convulsant  action  of  morphine  manifests 
itself.  Occasionally  we  find  individuals  who  are  almost  proof 
against  the  action  of  morphine,  and  who  take  large  doses  of  it 
without  any  apparent- effect.  Whether  in  these  persons  it  lowers 
the  temperature  as  it  does  in  pigeons  is  a  point  which  remains 
to  be  ascertained. 

By  means  of  experiments  upon  animals,  then,  we  are  able  to 
ascertain  the  action  of  drugs  upon  those  organs  of  the  body 
which  are  alike  in  man  and  animals ;  and  the  very  differences 
which  exist  between  the  various  sorts  of  animals,  help  us  to 
understand  the  action  of  drugs  more  thoroughly. 

Erroneous  Deductions  from  Experiments. — A  great  fault 
— and  one  which  is  only  too  common  in  the  works  of  experi- 
mental pharmacologists — is  that  of  drawing  general  conclusions 
from  limited  data. 

One  experimenter  tries  the  effect  of  a  drug,  let  us  say  tartar 
emetic,  upon  rabbits.  He  finds  that  they  do  not  vomit,  and  in- 
stead of  drawing  the  only  warrantable  conclusion,  viz.  that  tartar 

1  Lauder  Brunton, '  Action  of  Nitrite  of  Amyl  on  the  Circulation,'  Journal  of 
Anatomy  and  Physiology,  vol.  v.  p.  95. 


56  PHAEMACOLOGY  AND   THEEAPEUTICS.      [sect.  i. 

emetic  does  not  cause  vomiting  in  rabbits,  he  draws  the  general 
one — that  tartar  emetic  does  not  cause  vomiting  in  animals. 
Another  tries  it  upon  dogs,  and  he  finds  they  all  vomit.  Instead 
of  the  limited  conclusion  that  tartar  emetic  makes  dogs  vomit, 
he  draws  the  general  conclusion  that  it  makes  animals  in  general 
vomit.  The  two  observers  are  equally  positive  in  regard  to  their 
facts — each  is  assured  that  he  himself  is  right,  and  that  the  other 
is  totally  wrong.  The  reason  of  the  discrepancy  is  simply  that 
the  conditions  under  which  the  experiments  have  been  performed 
were  different,  but  the  observers  have  not  taken  these  differences 
into  account  when  drawing  their  conclusions.  A  third  observer 
then  comes,  perhaps,  and  by  further  experiments  reconciles  the 
apparently  contradictory  statements.  Thus  one  experimenter 
tries  the  effect  of  caffeine  upon  frogs  ;  he  finds  that  it  produces 
rigor  mortis  in  the  muscles.  Another  tries  the  same  drug,  and 
finds  no  such  result.  These  two  observations  are  completely 
contradictory,  until  a  third  tries  the  effect  of  the  drug  upon  two 
species  of  frog,  and  finds  that  while  the  muscles  of  the  rana 
esculenta  are  but  slightly  affected,  those  of  the  rana  temporaria 
are  rendered  rigid.1 

These  apparent  contradictions  in  the  results  of  different  ob- 
servers are  exceedingly  puzzling  to  the  student,  but  nothing  is 
more  instructive  to  those  who  are  actually  working  at  the  subject. 

The  utility  of  apparent  exceptions  was  fully  recognised  by 
Claude  Bernard,  who  says :  '  In  physiological  studies  we  must 
always  carefully  note  any  fact  which  does  not  accord  with  re- 
ceived ideas.  It  is  always  from  the  examination  and  the  dis- 
cussion of  this  exceptional  fact  that  a  discovery  will  be  made,  if 
there  is  one  to  make.' 2 

1  Schmiedeberg,  Arch.  f.  exper.  Path.  u.  Pharmalc,  Bd.  ii.  p.  C2. 
*  Bernard,  Ligwides  de  Vorgawisme,  torn.  i.  p.  258. 


57 


CHAPTEE  m. 

ACTION  OF  DEUGS  ON  PEOTOPLASM,  BLOOD,  AND  LOW 

OBGANISMS. 

Action  of  Drugs  on  Albumin. 

In  all  living  bodies  we  find  that  the  protoplasm  is  of  a  more  or 
less  albuminous  nature. 

Albuminous  substances  possess  a  very  complex  inter-mole- 
cular grouping,  and  very  high  atomic  weights.  Many  different 
forms  are  found  in  animals,  and  along  with  albumins  we  must 
associate  bodies  like  mucin,  which  probably  have  a  very  im- 
portant relation  to  it,  inasmuch  as  a  body  nearly,  if  not  quite, 
identical  with  mucin  forms  the  nucleus  of  the  red  blood-cor- 
puscles in  fowls,1  and  a  substance  of  an  allied  nature  also  occurs 
in  the  circulating  fluid  which  represents  the  blood  in  the  echino- 
dermata.2  The  albumin  of  serum  may  be  taken  as  a  representa- 
tive of  such  substances ;  it  is  soluble  in  water,  but,  at  a  certain 
temperature,  is  coagulated  and  precipitated.  It  is  coagulated 
also  by  alcohol,  but  if  the  coagulum  is  quickly  placed  in  water  it 
redissolves ;  if  allowed  to  remain  for  some  time  exposed  to  the 
action  of  the  alcohol  it  becomes  permanent  and  insoluble.  An 
insoluble  precipitate  also  falls  on  the  addition  of  tannic  acid, 
both  lead  acetates,  and  mercuric  chloride.  The  reagents  just 
mentioned  precipitate  all  the  albumins,  even  from  somewhat 
dilute  solutions ;  in  strong  solutions  precipitates  are  also  formed 
by  silver  nitrate,  copper  sulphate,  and  zinc  chloride. 

When  these  are  added  to  albumin  containing  only  a  small 
quantity  of  water,  as,  for  example,"  the  white  of  an  egg,  they 
form  with  it  a  solid  mass  of  albuminate.  A  small  quantity  of 
strong  potash  added  to  the  white  of  egg  produces  a  solid  trans- 
parent jelly  of  albuminate  of  potash,  and  a  similar  but  opaque 
jelly  is  formed  by  the  use  of  caustic  lime  or  baryta  in  the  place 
of  potash  :  these  albuminates  are,  however,  soluble  in  water. 

Albumin  dissolves  in  alkalies,  and  may  be  partly  precipitated 
by  neutralising.  The  alkaline  solution  is  not  coagulated  by  heat, 
and,  in  fact,  the  substance  present  in  the  solution  is  no  longer 
serum  albumin,  but  a  compound  of  the  albumin  with  the  alkali, 
or  alkali-albuminate. 

1  Lauder  Brunton  after  Kuhne,  Journ.  of  Anat.  and  Physiol.  Nov*  1869. 
*  Sehafer,  Proc.  Boy.  Soc,  vol.  xxxiv.,  p.  370. 


58  PHAKMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

Albumin  is  precipitated  by  a  small  quantity  and  dissolved 
by  excess  of  most  mineral  acids,  forming  witb  tbem  acid-albu- 
minates ;  thus  a  watery  solution  of  albumin  is  precipitated  by 
concentrated  nitric,  sulphuric,  or  hydrochloric  acid.  It  is  also 
precipitated  by  acetic  acid  along  -with  a  considerable  quantity  of 
a  neutral  salt  of  an  alkali  or  alkaline  earth,  or  of  gum  arabic  or 
dextrin.  This  precipitation  is  perhaps  best  marked  with  nitric 
acid,  but  it  only  occurs  with  moderate  quantities  of  nitric  acid. 
When  a  minute  quantity  only  of  the  acid  is  added,  no  precipita- 
tion takes  place,  and  the  solution  remains  clear ;  but  a  nitric- 
acid-albuminate  containing  a  small  quantity  of  acid  is  formed, 
and  if  the  solution  is  now  boiled  no  coagulum  will  form.  On  the 
addition  of  more  acid,  however,  a  second  nitric-acid-albuminate, 
insoluble  in  water,  is  produced,  and  a  precipitate  falls.  On  the 
addition  of  more  acid  still,  the  precipitate  is  redissolved,  and  a 
third  nitric-acid-albuminate  is  formed,  soluble  in  water,  and  not 
precipitated  on  boiling. 

The  temperature  at  which  albumin  coagulates  is  altered  by 
acids  and  alkalies.  Alkalies  generally  tend  to  raise  the  tempera- 
ture of  coagulation,  and  when  added  in  large  quantities  prevent 
it  altogether. 

Very  dilute  acetic  and  phosphoric  acid,  on  the  other  hand, 
tend  to  lower  the  coagulating  point,  although  large  quantities 
may  interfere  with  coagulation. 

Neutral  salts,  such  as  sodium  chloride  or  sulphate,  also  lower 
the  coagulating  point. 

The  organic  alkaloids  which  have  such  a  powerful  action  on 
the  animal  body  appear  to  resemble  acids  rather  than  alkalies 
in  their  effect  upon  albumin,  because,  according  to  Eossbach, 
they  lower  considerably  instead  of  raising  the  point  of  coagula- 
tion. 

Albumin  undergoes  an  extraordinary  change  in  consequence 
of  the  action  of  ozone,  and  becomes,  after  exposure  to  it,  un- 
coagulable  by  boiling,  and  by  acids,  excepting  in  large  quantities, 
and  by  metallic  salts,  with  the  exception  of  basic  acetate  of  lead, 
and  of  alcohol. 

The  action  of  alkaloids  upon  this  ozonised  albumin  is  even 
more  remarkable  than  upon  ordinary  albumin,  for  when  mixed 
with  it  in  Bmall  quantity,  they  restore  its  coagulability  to  the 
albumin,  and  cause  it  to  coagulate  far  under  the  boiling-point. 
When  added  to  the  albumin  before  exposure  to  a  stream  of  ozone, 
they  prevent  the  albumin  being  altered  by  it,  in  the  way  which 
it  would  otherwise  be,  and  it  remains  coagulable  by  heat,  in  the 
same  way  as  if  it  had  not  been  exposed  to  the  action  of  ozone  at 
all.  It  is  therefore  evident  that  the  alkaloids  not  only  increase 
the  coagulability  of  ordinary  albumin  at  a  high  temperature,  but 
that  they  act  upon  it  at  ordinary  temperatures  (S0°-40°  C.)  and 
destroy  its  affinity  for  ozone.   This  action  will  naturally  interfere 


ohap.  in.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.      59 

with  the  processes  of  oxidation  in  protoplasm ;  but  the  methods 
of  examining  this  action  will  be  described  later  on  (p.  69). 

When  a  solution  of  pure  albumin  is  added  to  a  mixture  of 
guaiac  and  vegetable  protoplasm,  it  greatly  lessens  the  blue 
colour,  which  would  otherwise  be  produced.  The  cause  of  this 
appears  to  be  that  albumins  or  albuminous  substances  have 
such  an  affinity  for  ozone  that  they  take  it  up  instead  of  allowing 
it  to  act  on  the  guaiac.  This  affinity  for  ozone  is  diminished  by 
the  action  of  alkaloids. 

This  is  shown  by  taking  several  tubes  containing  an  albuminous  solution 
of  a  certain  strength.  .Reserving  one  as  a  standard,  the  alkaloids  are  added 
to  the  others,  and  after  a  certain  time  has  elapsed,  so  as  to  allow  the  alkaloid 
to  affect  the  albumin,  a  small  quantity  of  lettuce  water  is  mixed  with  each, 
and  then  a  little  guaiac.  In  the  standard  one  the  colour  will  he  least,  because 
the  albumin  not  having  been  acted  upon  by  the  alkaloids  will  interfere  with 
the  reaction  of  the  lettuce  water  and  the  guaiac  upon  each  other.  In  the 
others  a  blue  colour  will  appear  with  greater  or  less  intensity,  according  as 
the  albumin  has  been  more  or  less  affected  by  the  alkaloid.  This  experi- 
ment, however,  is  not  free  from  fallacy,  because  there  is  to  be  considered  not 
merely  the  action  of  the  alkaloid  upon  the  albumin,  but  its  action  on  the 
protoplasm  as  well,  and  it  is  therefore  advisable  to  use  it  in  a  quantity  which 
is  small  as  compared  with  the  amount  of  albumin  employed.1 

Action  of  Drugs  on  Protoplasmic  Movements. 

The  amoeba  consists  of  a  small  mass  of  structureless  proto- 
plasm, without  any  distinct  cell-wall. 

It  contains  numerous  granules  and  nucleus,  with  nucleolus, 
as  well  as  one  or  more  vacuoles,  which  appear  to  be  small  spaces 
filled  with  fluid. 

Some  amcebse  live  in  salt  water,  others  in  fresh  water  ;  and, 
although  it  may  be  impossible  with  the  microscope  to  detect  any 
marked  difference  between  them,  they  exhibit  a  great  difference 
in  their  reactions  to  drugs — the  salt-water  amcebse  being  only 
slightly  affected  by  them,  while  fresh-water  amcebse  are  readily 
susceptible  to  their  action. 

The  amceba  is  nourished  by  simply  adhering  to  any  particle 
of  food,  closing  over  it  and  digesting  it,  and  afterwards  opening 
and  ejecting  the  residue. 

This  protoplasmic  mass  is  almost  constantly  altering  in 
shape,  pushing  out  projections  at  one  point,  and  drawing  them 
in  at  another.  By  this  means,  also,  it  moves  about  from  place 
to  place, 

Method    of    Experimentation    on    Amoebae    and    leucocytes. — In 

experimenting  on  amcebse,  take  a  drop  of  slimy  sediment,  such  as  is 
found  in  the  tanks  of  hothouses,  and  place  it  on  the  covering-glass  of  a 
microscope  ;  this  may  then  either  be  put  on  an  object-glass,  and  the  excess 
of  water  removed  by  filter -paper,  or,  still  better,  it  may  be  inverted  over  the 
opening  of  a  Strieker's  warm  stage. 

1  Bossbach,  Yerhandl.  d.  phys.  med,  Oes.  zu  Wilrzburg,  N.P.,  Band  iii.  p.  346. 


60  PHABMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

"When  it  is  simply  laid  on  the  object-glass,  a  solution  of  the  drug  is  added 
by  putting  a  drop  across  the  edge  of  the  covering-glasB,  and  allowing  it  to  be 
drawn  gradually  underneath  by  capillary  attraction. 

Gases  are  best  applied  by  means  of  a  Strieker's  stage,  which  is  also  con- 
venient for  experiments  on  solutions. 

In  experimenting  on  leucocytes  with  the  aid  of  this  stage,  a  covering-glass 
is  applied  to  the  cut  surface  of  a  newt's  tail,  or  to  the  surface  of  a  drop  of 
blood,  so'  that  a  very  minute  quantity  of  blood  adheres  to  it. 

The  drug  to  be  tested  is  kept  dissolved  in  a  -65--75  per  cent,  solution  of 
common  salt  (Na  CI).  The  salt  solution  of  this  strength  is  often  called 
simply  normal  salt  solution,  and  is  used  instead  of  water,  because  water  itself 
has  a  very  destructive  action  on  those  forms  of  protoplasm,  which  are  usually 
nourished  by  saline  solutions,  like  blood  or  serum. 

A  drop  of  the  salt  solution  containing  the  drug  is  placed  over  the  blood  on 
the  covering-glass,  and  inverted  over  the  warm  stage  as  already  described. 
If  the  experiment  is  to  continue  long,  a  rim  of  oil  should  be  drawn  around 
the  edge  of  the  covering-glass  with  a  camel-hair  pencil,  so  as  to  prevent 
evaporation. 

The  advantage  of  using  such  a  small  quantity  of  blood  is,  first,  that  it 
mixes  rapidly  and  perfectly  with  the  solution  ;  and  secondly,  that  it  does  not 
dilute  the  solution  of  the  drug,  and  we  thus  know  the  strength  of  the  drug  used. 

If  we  used  a  large  drop  of  blood,  we  should  have  to  employ  a  solution  of 
the  drug  twice  the  strength  we  desire,  so  that  when  a  drop  of  equal  size 
was  added  to  the  blood,  the  mixture  would  contain  the  proper  proportion. 

Amoebae. — The  effect  of  heat  and  cold  upon  the  movements 
is  very  marked,  cold  rendering  them  slow,  or  arresting  them 
altogether.  Heat  at  first  greatly  quickens  their  movements,  but 
when  raised  to  35°  C.  it  causes  them  to  fall  into  a  state  of  tetanic 
contraction  and  assume  a  spherical  form. 

This  state  is  one  of  heat-tetanus,  and  if  the  temperature  be 
now  reduced,  the  movements  will  again  reappear. 

At  a  temperature  of  40°  C.  they  also  become  spherical  and 
motionless.  But  their  movements  do  not  return  when  the  tem- 
perature is  reduced ;  they  are  in  a  state  of  heat-rigor,  the  high 
temperature  having  coagulated  the  protoplasm. 

Slight  electrical  shocks  from  a  coil  increase  the  rapidity  of 
the  protoplasmic  movements ;  stronger  ones  cause  tetanic  con- 
traction ;  and  numerous  or  powerful  ones  produce  coagulation. 

Common  salt  in  very  small  quantity  (a  drop  of  1  per  cent, 
solution  slowly  added)  first  quickens  the  protoplasmic  movements 
and  then  causes  sudden  tetanic  contraction,  and  the  expulsion  of 
any  food  they  may  contain  at  the  moment,  and  sometimes  even 
expulsion  of  the  nucleus. 

When  water  is  added  so  as  again  to  dilute  the  mixture  the 
amoebae  resume  their  movements. 

Both  acids  and  alkalies,  when  very  dilute,  increase  the  proto- 
plasmic movements  and  afterwards  arrest  them. 

Hydrochloric  acid  has  a  more  powerful  action  than  a  solution 
of  potash  of  a  similar  strength.  It  causes  the  amoeba  to  contract 
and  form  a  ball  with  a  sharp  double  contour.  In  it,  twitching 
movements  first  occur,  which  expel  any  food  present.  It  then 
becomes  pale  and  lumpy,  and  breaks  up. 


chap,  in.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.      61 

Potash  causes  them  to  swell  up  and  assume  the  form  of  large 
pale  vesicles,  which  quickly  burst. 

A  constant  current  of  electricity  causes  contraction  and 
imperfect  tetanus ;  and,  if  powerful  and  long  kept  up,  the  posi- 
tive pole  produces  in  the  amoebae  near  it  the  same  changes  as 
dilute  hydrochloric  acid,  and  the  negative  pole  the  same  changes 
as  are  produced  by  an  alkali  such  as  potash. 

Oxygen  appears  to  be  necessary  for  their  life ;  its  removal 
by  means  of  hydrogen  deprives  the  amoebae  of  their  power  of 
motion,  and  finally  causes  contraction  and  coagulation. 

Carbonic  acid  alone  has  a  similar  action  to  removal  of  oxy- 
gen and  produces  this  effect  both  in  the  presence  and  absence 
of  oxygen,  but  takes  a  longer  time  to  do  so  when  oxygen  is 
present.1 

Leucocytes. — In  their  appearance  and  movements  leucocytes 
strongly  resemble  amoebae :  they  are  affected  in  a  similar  manner 
by  heat,  electricity,  and  drugs.  Their  resistance  to  the  action 
of  drugs  varies  somewhat  in  different  animals.  Those  obtained 
from  the  blood  of  the  newt,  for  example,  are  more  resistant  than 
those  of  the  guinea-pig,  and  those  of  the  female  newt  more  re- 
sistant than  those  of  the  male,  to  the  action  of  quinine.2  Heat 
and  cold  affect  the  movements  of  leucocytes  in  very  much  the 
same  way  as  those  of  amoebae. 

The  movements  of  leucocytes,  like  those  of  amoebae,  are  of 
two  kinds,  viz.  movements  of  the  protoplasmic  pseudopods, 
while  the  leucocyte  remains  in  situ.  The  pseudopods  in  this 
instance  are  generally  of  a  waxy  look  and  knoblike  form. 

Secondly,  movements  of  migration  from  place  to  place ;  these 
movements  are  accompanied,  or  accomplished,  through  the 
projection  of  numerous  fine  filaments. 

Effect  of  Drugs.—  Cinchona  alkaloids — quinine,  quinidine, 
cinchonine,  and  cinchonidine  have  a  remarkable  power  of  arrest- 
ing these  movements  in  the  proportion  of  1  in  1,500.  They 
quickly  stop  the  migratory  movements  of  leucocytes  from  the 
newt,  and  in  a  much  larger  proportion  will  arrest  the  movements 
of  the  knoblike  pseudopods. 

No  very  marked  difference  is  observed  in  the  strength  of  the 
cinchona  alkaloids,  though  quinine  seems  to  be  somewhat  the 
most  powerful. 

Sulphate  of  bebeerine  is  almost  as  powerful  as  the  cinchona 
alkaloids. 

Strychnine  is  very  much  less  powerful  than  any  of  the  alka- 
loids mentioned. 

Potassium  picrate  and  aesculin  have  but  little  action,3 


1  Kuhne,  Protoplasma  wnd  Contractilitat,  pp.  28-53. 

2  Geltowsky,  Practitioner,  vol.  viii.  pp.  325-330. 
*  Buchanan  Baxter,  Practitioner,  vol.  xi.  n.  321. 


62  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

Movements  of  Leucocytes  in  the  Blood-vessels. — In  the 

processes  of  inflammation  leucocytes  pass  in  great  numbers 
through  the  walls  of  the  capillaries. 

The  effect  of  quinine  in  arresting  their  movements,  when 
mixed  with  them  directly,  naturally  leads  one  to  expect  that  it 
may  arrest  their  migration  from  the  capillaries,  when  injected 
into  the  blood,  and  this  anticipation  has  been  realised  in  the 
experiments  of  Professor  Binz. 

To  observe  this  phenomenon  the  brain  of  a  frog  is  to  be  destroyed,  and 
a  little  curare  injected  under  the  skin,  in  order  to  abolish  any  spinal  reflex 
movements.  It  is  then  laid  on  »  piece  of  cork,  such  as  that  shown  in 
Fig.  8,  with  a  hole  at  one  side,  over  which  a  piece  of  glass  is  fastened  about 


Fig.  8. — Apparatus  for  examining  the  mesentery  of  the  frog  under  the  microscope. 

half  an  inch  higher,  by  means  of  two  other  pieces  of  cork  and  some  sealing- 
wax.  On  this  a  piece  of  sheet  cork  of  the  form  shown  in  the  figure,  and  a 
round  piece  of  glass  are  cemented  so  as  to  form  a  channel,  in  which  the 
intestine  lies.  The  body  of  the  frog  is' fixed  to  the  cork,  the  abdomen 
opened,  the  intestines  drawn  out,  and  the  mesentery  •  fastened  with  very 
fine  pins  over  the  aperture.  In  half  an  hour,  or  two  hours,  the  leucocytes 
pass  rapidly  through  the  walls  of  the  capillaries,  and  afterwards  wander 
through  the  tissues. 

The  drug  may  then  be  injected  into  the  lymph-sac,  or  locally  applied  to 
the  mesentery. 

When  quinine  is  applied  locally  to  the  mesentery  in  this 
condition  it  arrests  the  movements  of  the  leucocytes,  which  have 


Fig.  9.— Diagram  to  illustrate  the  action  of  quinine  on  leucocytes,  modified  from  Binz  (Das  Wesen 
del-  Chininmrkung.  Berlin,  1868).  The  thick  lines  represent  the  walls  of  the  blood-vessel,  and 
numerous  leucocytes  are  shown  both  inside  it  and  outside  distributed  through  the  adjoining 
tissues,  a  represents  the  vessel  before,  aud  6  after,  the  local  application  of  quinine.  The  leuco- 
cytes outside  the  vessel  have  their  movements  arrested,  and  cannot  wander  on  through  the 
tissues,  while  those  inside  are  not  affected  and  continue  to  emigrate,  c  represents  the  effect  of 
quinine  injected  into  the  circulation  or  lymph-sac.  The  leucocytes  inside  the  vessel  are  here 
affected  first,  and  their  emigration  stopped,  while  those  outside  still  continue  to  travel  onwards. 

already  emerged,  but  does  not  prevent  those  which  are  still 
within  the  vessels  from  going  out ;  they  therefore  form  a  dense 
accumulation  around  the  vessel  (Fig.  9,  b).    When  injected  into 


chap,  in.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.      63 

the  circulation,  on  the  contrary,  the  leucocytes  which  are  in  the 
vessels  are  prevented  from  passing  from  the  capillaries,  while 
those  which  have  already  passed  out  continue  to  wander  on- 
wards, and  thus  a  dear  space  is  left  outside  the  vessel  (Fig.  9,  c). 

The  quantity  of  quinine  necessary  to  produce  this  effect  is 
a5Soi)^  *°  io'oo^  °f  the  animal's  weight. 

If  quinine  were  given  to  stop  the  exit  of  leucocytes  from  the 
vessels  in  peritonitis,  three  or  four  grammes  would  be  required 
to  be  given  within  a  short  time,  to  a  man  weighing  150  lbs. 

In  guinea-pigs  a  dose  of  quinine  sufficient  to  kill  the  animal 
does  not  stop  the  movements  of  the  leucocytes  in  its  blood, 
which  are  seen  to  go  on,  when  a  drop  of  it  is  examined  after 
death. 

Red  Blood  Corpuscles. — The  size  of  the  red  corpuscles  is 
diminished  by  carbonic  acid,  by  morphine,  or  by  warmth,  either 
applied  locally  on  the  hot  stage  of  a  microscope,  or  acting  on 
them  in  the  vessels  of  an  animal  suffering  from  fever. 

It  is  increased  by  oxygen,  hydrocyanic  acid,  quinine,  or  cold ; 
and  an  increase  occurs  also  in  eases  of  anaemia.1 

The  red  corpuscles  pass  out  of  the  capillaries  like  the  white, 
but  they  do  so  very  slowly  indeed,  and  in  small  numbers,  under 
ordinary  circumstances.  Excess  of  sodium  chloride  in  the  blood 
causes  them  to  pass  out  much  more  quickly  ; 2  and  rattle-snake 
poison,  when  locally  applied,  produces  such  sudden  extravasation 
that  it  is  impossible  to  follow  the  process :  the  whole  field  of  the 
microscope  becoming  suddenly  covered  with  blood.3 

Action  of  Drugs  on  Infusoria. 

Among  the  infusoria,  like  the  amcebse,  each  individual  consists  of  a  single 
mass  of  protoplasm,  and  not  of  a  number  of  distinct  cells ;  but  the  proto- 
plasm is  differentiated.  Kound  the  greater  part  of  the  animal  it  seems  to 
be  somewhat  harder,  so  as  to  form  a  sort  of  skin,  excepting  at  one  place 
which  is  softer  than  the  rest,  serving  for  the  ingress  of  food  and  the  egress 
of  egesta. 

Instead  of  throwing  out  pseudopods,  the  body  is  either  covered  entirely 
with  cilia  or  they  are  arranged  round  the  mouth.  Once  it  has  entered  by 
the  mouth,  the  food  finds  its  way  all  through  the  protoplasm  of  the  body. 

A  contractile  vesicle  exists,  which  pulsates  rhythmically. 

Mode  of  Experimentation.  —  For  the  purpose  of  examining  the 
action  of  drugs  upon  infusoria  an  infusion  of  hay  ia  prepared  some  days 
previously.  Two  small  pipettes  are  then  made,  which  will  deliver  drops 
of  equal  size. 

This  is  done  by  heating  a  piece  of  glass  tubing  in  the  middle,  drawing 
it  out,  and  cutting  it  across  by  a  scratch  with  a  triangular  file  (Fig.  10). 
With  one  of  these  a  drop  of  hay-infusion  is  placed  on  the  covering-glass, 
which  is  inverted  on  a  Strieker's  stage  and  examined.    In  order  to  ascertain 

1  Manassein,  Ueber  die  Dimensioned,  der  Blutlcorperchen  writer  verschiedenen 
Einflussen.    Tubingen,  1872. 

2  Prussak,  Wiener  Akad.  SiUungsber.l\i.,  1876  (Abth.  2),  p.  13. 
'  Brunton  and  Fayrer,  Proc.  Roy.  Soc,  February  1875,  p.  271. 


64  PHAKMACOLOGY  AND   THEKAPEUTICS.      [sect.  I. 

the  lethal  strength  of  a  drug,  a  drop  of  a  solution  of  the  poison  of  a  definite 
strength  is  then  mixed  with  it,  and  the  infusoria  are  examined  again  after  a 


certain  time. 


Fig.  10. — Diagram  to  show  the  way  o£  making  small  pipettes. 

If  they  continue  moving,  another  experiment  is  made  with  a  stronger 
solution  ;  but  if  they  have  completely  stopped,  it  is  repeated  with  a  weaker 
one  until  the  solution  is  of  such  »  strength  that  the  movements  become 
very  slight  and  cease  almost  immediately  after  mixing,  and  cannot  be 
restored  by  the  addition  of  water.  As  the  two  drops  of  fluid  were  of 
equal  size,  the  lethal  strength  of  the  solution  is  just  one  half  of  that  which 
was  last  added.  By  repeating  the  experiments  in  exactly  the  same  way 
with  different  drugs,  their  relative  poisonous  properties  are  ascertained. 

Heat  increases  the  rapidity  both  of  the  rhythmical  contrac- 
tions of  the  vesicle  and  of  the  ciliary  motion  and  consequently  of 
the  movements  from  place  to  place  of  the  infusoria.  It  seems  as 
if  the  cilia  were  not  equally  affected  by  heat,  those  which  pro- 
duce a  longitudinal  movement  appearing  to  be  acted  upon  more 
quickly  than  those  which  cause  a  movement  of  rotation.  Both 
kinds  are  first  stimulated  and  then  paralysed. 

At  temperatures  between  25°  and  30°  G.  the  contractions  of 
the  vesicle  are  greatly  quickened,  and  the  animal  moves  with 
great  rapidity  in  the  longitudinal  direction. 

Between  30°  and  35°  its  movements  are  still  very  rapid,  but  it  seems  to 
have  lost  the  power  of  direction ;  all  the  cilia  seem  in  full  action,  and  the 
movements  of  the  individual  are  determined  simply  by  their  anatomical 
arrangement. 

Above  40°  the  cilia,  which  act  longitudinally,  appear  to  have  stopped  and 
the  animal  rotates,  at  first  very  rapidly,  then  slower  and  slower  until  all 
movements  cease,  and  the  protoplasm  appears  to  become  fluid ;  but  when 
the  heat  is  still  further  raised  it  coagulates.1 

Cold  lessens  the  quickness  of  the  rhythmical  contractions  of 
the  vesicle,  of  the  ciliary  motion  and  of  the  movements  from 
place  to  place.  Weak  electrical  currents  first  quicken  the  ciliary 
motion  and  cause  movements  of  rotation,  then  swelling  of  the 
protoplasm,  slower  movements,  and  finally  apparent  solution  of 
the  protoplasm. 

Moderate  currents  produce  a  tetanic  contraction  of  the  proto- 
plasm and  of  the  cilia,  while  the  contractile  vesicle  is  unaffected. 

Strong  currents  cause  liquefaction  of  the  protoplasm. 

Saline  solutions  appear  rather,  if  we  may  say  so,  to  alter 
the  conditions  under  which  the  infusoria  live  than  to  affect  the 
protoplasm  itself.      Strong  solutions  cause  them  to  shrivel  and 


1  Eossbach, '  Die  rhythmischen  Bewegungserscheinungen  der  einf achsten  Organ- 
ismen,'Verh.  d.Wursburgerphysik.  med.  Gesellsch.  A.N.P.,  Bd.  ii.,  Separat-Abdruck 
S.  23.  This  work  contains  a  number  of  exceedingly  interesting  and  valuable 
observations  on  the  subject. 


chap,  m.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.      65 

then  to  swell  up  and  become  motionless.  This  effect  appears  to 
be  due  to  the  solution  altering  the  quantity  of  water  which  the 
protoplasm  contains. 

Weaker  saline  solutions,  on  the  contrary,  quicken  their  move- 
ments, and,  instead  of  causing  them  to  shrivel,  make  them  swell 
up  at  once.  Chloride  of  sodium,  chloride,  bromide,  and  chlorate 
of  potassium,  as  well  as  alum,  all  have  this  effect. 

Acids  in  minute  quantities  cause  contraction  both  of  the 
body  and  of  the  vesicle.  The  ciliary  motion  is  at  first  quickened 
and  then  retarded ;  the  rate  of  contraction  of  the  vesicle  is  at 
once  diminished. 

Moderate  quantities  cause  coagulation  of  the  protoplasm  with 
swelling  and  liquefaction  after  death. 

Strong  acids  at  once  destroy  the  protoplasm. 

Alkalies  in  minute  quantities  cause  swelling  of  the  proto- 
plasm, dilatation  and  slowness  of  the  contractile  vesicle. 

Moderate  quantities  at  once  arrest  the  movements,  cause 
liquefaction  of  the  protoplasm,  and  destroy  its  differentiation, 
the  contractile  vesicles  and  vacuoles  disappearing.  They  then 
cause  swelling,  and  finally  solution. 

In  large  quantities  they  produce  immediate  liquefaction  of  the 
whole  body. 

Other  drugs  appear  to  affect  the  protoplasm  itself,  a*id 
arrest  its  movements  without  producing  any  apparent  change 
in  it. 

The  most  active  are  chlorine,  bromine,  corrosive  sublimate, 
iodine,  permanganate  of  potassium,  and  creasote. 

Quinine  is  much  less  powerful  than  these,  though  it  is  much 
more  so  than  most  other  organic  alkaloids.  Strychnine  has  only 
one-fourth  the  power  of  quinine. 

Cobra  poison  at  first  greatly  quickens  the  movements  of 
infusoria  and  then  arrests  them,  causing  just  before  death  a  con- 
traction of  the  protoplasm,  which  then  expands  to  its  ordinary 
size. 

Relations  of  Motion  and  Oxidation. 

All  animals,  from  the  lowest  to  the  highest,  evidence  their 
life  by  motion  at  one  time  or  another  ;  and  the  energy  required 
for  this  motion  is  maintained  by  processes  of  combustion. 

The  materials  for  this  combustion,  viz.  oxygen,  and  fuel  of 
some  sort,  or  food,  are  derived  from  the  external  medium  in 
which  the  animal  lives ;  and  in  order  to  enable  these  substances 
to  be  available  for  each  part  of  the  animal  body,  we  must  have 
some  kind  of  respiration  and  circulation  going  on  in  it. 

In  unicellular  organisms,  consisting  of  a  single  mass  of  proto- 
plasm, the  oxygen  is  derived  from  the  water  in  which  they  swim, 
and  both  it  and  the  nutritive  material  derived  from  the  digestion 


•66  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

of  enclosed  masses  are  circulated  through  the  protoplasm  by 
contractile  vacuoles. 

In  sponges,  where  the  organism  no  longer  consists  of  one  but 
of  several  cells  united  into  a  community,  some  of  these  are  fur- 
nished with  cilia,  in  order  to  send  a  current  containing  oxygen 
and  food  to  the  other  cells  having  a  less  favoured  position. 

In  higher  animals,  where  many  cells  are  built  up  to  form  one 
organism,  we  find  a  circulatory  and  respiratory  apparatus  fully 
developed. 

The  medium  in  which  unicellular  organisms  live  is  the  water 
in  which  they  swim.  The  medium  in  which  the  cells  composing 
the  main  parts  of  the  bodies  of  higher  animals,  such  as  man, 
live,  is  not  the  air  which  surrounds  the  body,  but  the  intercellular 
fluid  in  which  the  cells  themselves  are  bathed. 

As  Claude  Bernard  points  out  with  his  usual  clearness,  the 
cells  of  the  human  body  and  the  lowest  unicellular  organisms 
alike  live  in  a  liquid  medium.  From  the  layer  of  fluid  surround- 
ing it,  the  cell  takes  up  the  oxygen  and  food  which  this  layer  can 
yield.  The  supply  being  exhausted,  a  unicellular  organism  can 
move  on  elsewhere,  but  the  cells  in  higher  animals,  being  fixed 
and  unable  to  move,  require  fresh  portions  of  oxygen  and  of 
aiutritive  fluid  to  be  brought  to  them. 

•  This  is  effected  by  the  slow  circulation  of  the  lymph  in  which 
the  cells  themselves  are  bathed  and  by  the  supply  to  the  lymph 
<of  oxygen  and  nutritive  material  from  the  blood. 

The  circulation  of  the  lymph  is  aided  in  many  lower  or- 
ganisms by  the  motion  of  cilia,  and  this  is  found  persisting  in 
:some  parts  of  the  higher  animals,  e.g.  the  central  canal  of  the 
spinal  cord. 

Between  the  blood  and  the  lymph  an  interchange  goes  on, 
oxygen  passing  from  the  blood  to  the  lymph  or  intercellular  fluid, 
and  carbonic  acid  from  the  lymph  to  the  blood. 

This  interchange  of  gases  between  the  blood,  the  intercellular 
fluid,  and  the  cells  is  termed  internal  respiration. 

In  order  to  maintain  this,  a  constant  current  of  blood  must 
take  place ;  and  when  its  circulation  is  locally  arrested  it  becomes 
deprived  of  oxygen  and  loaded  with  carbonic  acid,  so  that  the 
•cells  in  the  district  in  which  the  stagnation  occurs  suffer  from 
local  asphyxia,  while  the  other  parts  of  the  body  may  be  perfectly 
healthy. 

When  the  general  circulation  is  arrested  by  stoppage  of  the 
heart,  by  obstruction  of  the  pulmonary  arteries,  or  by  the  rup- 
ture of  an  aneurism  draining  the  blood  away,  the  whole  body 
suffers  in  a  similar  manner  from  general  asphyxia  by  the  cessa- 
tion of  internal  respiration. 

If  oxygen  were  simply  dissolved  in  the  blood,  the  quantity 
which  would  be  conveyed  to  the  tissues  would  be  too  small  for 
their  wants,  and  we  therefore  have  as  an  oxygen-carrier  a  sub- 


chap,  in.]    ACTION  OP  DRUGS  ON  PROTOPLASM,  ETC.      67 

stance  capable  of  taking  up  a  large  quantity  of  oxygen,  of  readily 
forming  a  loose  compound  with  it>  and  of  again  giving  it  off 
readily  to  oxidisable  substances. 

In  man  and  mammals  and  many  of  the  lower  animals  this 
substance  is  haemoglobin  containing  iron.  In  some  annelids  it  is 
a  green  substance,  chlorocruorin ;  and  in  the  octopus  and  some 
crustaceans  it  is  a  blue  body,  hsemocyanin,  containing  copper.1 

In  order  to  remove  carbonic  acid  taken  up  from  the  tissues 
and  obtain  a  fresh  supply  of  oxygen,  an  interchange  takes  place 
between  the  blood  and  the  external  air  in  the  lungs;  this  is 
external  respiration.  Without  any  direct  influence  being  ex- 
erted upon  the  cells  of  the  animal  body  themselves,  they  may  be 
affected  and  their  nutrition  greatly  modified  by : 

1st.  Alterations  in  the  circulation  of  the  intercellular  fluid  or 
lymph  in  which  they  are  bathed. 

2nd.  In  the  greater  or  less  rapidity  of  circulation  of  blood 
locally. 

3rd.  In  the  circulation  generally,  from  changes  in  the  heart 
and  blood-vessels  generally. 

4th.  Changes  in  the  oxygen-carrying  power  of  the  blood, 
either  from  alterations  in  its  power  to  take  up  or  give  off  oxygen. 

5th.  Changes  in  the  external  respiration. 

All  these  conditions  may  be  altered  by  drugs,  or  at  least  by 
therapeutic  measures.  Thus  the  circulation  of  lymph  in  a  part 
may  be  increased  by  shampooing,  and  its  accumulation  in  a 
case  of  dropsy  may  be  removed  by  incision,  by  puncture,  or  by 
drainage. 

The  circulation  of  blood  may  be  arrested  locally  and  gangrene 
induced  by  the  continuous  use  of  ergot.  It  may  be  increased  by 
the  use  of  local  stimulants  or  irritants. 

The  circulation  generally  may  be  affected  by  the  large  class  of 
vascular  stimulants  and  depressants,  to  be  afterwards  discussed, 
and  sometimes  by  stoppage  of  the  pulmonary  circulation  through 
minute  emboli. 

Alterations  in  the  oxygen-carrying  power  of  the  blood  will 
be  discussed  presently,  and  those  in  the  external  respiration 
subsequently. 

Oxidation  of  Protoplasm. — The  movements  of  protoplasm 
are  intimately  connected  with  processes  of  oxidation  going  oh , 
in  it. 

By  these  processes  chemical  energy  is  converted  into  the 
mechanical  energy  exhibited  in  the  movements,  and  this  is 
sometimes  very  considerable. 

The  oxygen  which  takes  part  in  these  processes  is  not  always 
derived  from  the  surrounding  medium  at  the  exact  moment  when 

1  For  further  details  see  Physiological  Chemistry,  by  A.  Gamgee,  vol.  i.,  1880, 
p.  130. 

f  2 


68  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

"the  movements  take  place ;  it  may  have  been  obtained  some  time 
before,  and  the  movements  may  continue  for  a  little  while  after 
all  oxygen  has  been  removed. 

It  therefore  appears  that  protoplasm  has  the  power  of  ab- 
sorbing and  storing  up  within  itself,  in  some  manner  or  other, 
oxygen,  which  it  can  afterwards  utilise  for  the  purpose  of  liberat- 
ing mechanical  energy. 

This  storage  of  oxygen  takes  place  not  only  in  the  proto- 
plasm of  unicellular  organism,  but  also  in  the  tissues  of  the 
higher  animals,  e.g.  the  muscles. 

The  exact  way  in  which  storage  occurs  is  not  known,  but  it 
has  been  well  compared  by  Professor  Ludwig  to  the  storage  of 
oxygen  in  gunpowder.  The  oxygen  is  there  contained  in  the 
nitrate  of  potassium,  a  compound  which  is  readily  decomposable 
by  the  application  of  heat,  and  then  gives  rise  to  the  evolution  of 
mechanical  energy ;  and  this  it  does  perfectly  well  in  an  enclosed 
Bpace,  like  a  gun-barrel,  where  no  air  is  present. 

The  power  of  storing  up  oxygen  is  very  limited,  and  although 
protoplasmic  movements  continue  for  a  little  while  after  all  ex- 
ternal oxygen  has  been  removed,  yet  they  will  not  continue  long. 

A  convenient  way  of  ascertaining  this  fact  has  been  devised  by  Ktihne, 
•who  adds  a  small  quantity  of  blood  or  of  haemoglobin  solution  to  a  drop  of 
water  containing  protoplasmic  organisms  or  cells  placed  on  a  covering-glass. 
This  is  then  observed  with  a  micro-spectroscope.  The  haemoglobin  solution 
exhibits  the  two  bands  characteristic  of  oxy-hsemoglobin.  When  all  the 
oxygen  is  removed  by  means  of  a  stream  of  hydrogen,  kept  up  for  some 
time,  the  spectrum  of  oxy -haemoglobin  passes  into  that  of  reduced  haemo- 
globin. 

The  occurrence  of  this  change  indicates  the  moment  when  all  the  oxygen 
has  disappeared  from  the  liquid.  By  reckoning  from  this  moment  onwards, 
we  are  able  to  estimate  the  length  of  time  during  which  the  movements 
continue  in  the  absence  of  oxygen. 

Oxygen-carrying  Power  of  Protoplasm. — Not  only  does 
protoplasm  possess  the  power  of  taking  up  oxygen  readily  and 
assimilating  it  to  itself,  but  it  has  also  the  power  of  taking  up 
and  giving  off  oxygen  to  other  substances  when  these  substances 
would  be  unable  to  take  it  themselves. 

We  may  understand  this  action  better  by  comparing  it  in  a 
very  rough  way  with  that  of  a  man  whose  greater  strength 
enables  him  to  seize  fruit  or  break  off  pieces  of  sweatmeat  and 
give  them  to  his  child,  which  thus  enjoys  what  it  could  not  have 
obtained  for  itself,  however  desirous  of  them  it  might  be. 

.Method  of  Experimenting'. — Guaiae  resin,  when  finely  divided  and 
oxidised,  becomes  of  a  blue  colour.  It  has,  however,  only  a  slight  power 
of  attracting  oxygen  to  itself  from  the  air,  or  from  water  in  which  the 
oxygen  is  dissolved,  and  thus  the  blue  colour  is  developed  slowly. 

On  the  addition  of  protoplasm  to  the  water  containing  the  guaiae,  the 
blue  colour  is  developed  rapidly.  The  reason  of  this  possibly  is,  that  the 
protoplasm  has  taken  up  oxygen  from  the  water  and  given  it  over  to  the 
guaiae.  This  process  reminds  us  of  the  action  of  spongy  platinum  in  causing 
oxidation  of  hydrogen  or  formic  acid. 


chap,  iii.]    ACTION  OF  DEUGS  ON  PROTOPLASM,  ETC.      69 

Ozonising  Power  of  Protoplasm.— It  has  been  supposed 
that,  in  addition  to  its  power  of  oxidising  such  substances  as 
guaiac  by  giving  to  them  oxygen  which  it  has  already  taken  up, 
protoplasm  has  the  power  of  actually  breaking  up  the  molecules 
of  oxygen  and  forming  ozone. 

The  rapid  oxidation  which  protoplasm  causes  has  been  at- 
tributed to  this  power.  A  similar  action  to  this  is  observed 
during  the  slow  oxidation  of  phosphorus.  Phosphorus  appears 
to  break  up  the  molecule  of  oxygen,  taking  to  itself  one  atom 
and  freeing  another,  which  unites  with  two  more  in  order  to 
form  ozone. 

Action  of  Drug's  on  Oxidation. — A  convenient  way  of  testing  the 
effect  of  drugs  upon  oxidation  is  to  use  the  protoplasm  of  potato,  of  lettuce, 
or  of  dandelion.  The  most  active  part  of  the  potato  lies  just  under  the 
skin,  as  is  seen  by  pouring  some  freshly  prepared  tincture  of  guaiac  over 
its  cut  surface.  A  ring  of  blue  first  forms  close  to  the  skin,  and  is  always 
darkest  there,  although  it  may  extend  over  the  whole  of  the  cut  surface.  The 
ammoniated  tincture  of  the  British  Pharmacopoeia  will  not  answer.  The 
tincture  must  be  made  with  spirit  only.  When  potato  is  used,  the  whole  of 
the  potato  may  be  pounded  with  water,  or,  still  better,  the  peel  alone  may  be 
cut  off  and  rubbed  up  with  water  in  a  mortar  and  then  filtered  through 
linen.    When  lettuce  or  dandelion  is  used,  the  fresh  leaves  are  triturated 


Pig.  11.— Test-glasses  for  examining  the  action  of  drags  on  oxidation. 

in  a  mortar  with  five  or  ten  times  their  bulk  of  water,  and  the  solution  is 
then  filtered.  A  row  of  test-tubes  or  test-glasses  having  been  prepared, 
a  measured  quantity  of  water  is  put  into  the  first.  In  this  glass  the 
protoplasm  is  not  mixed  with  any  foreign  substance,  and  it  therefore 
serves  as  the  standard  with  which  to  compare  the  others ;  and  into  the 
others  is  put  a  similar  quantity  of  solutions  of  the  drugs  to  be  tested. 
Each  test-glass  is  distinguished  by  a  label  bearing  either  a  number  or  the 
name  of  the  drug  which  it  contains  attached  to  it.  To  each  glass  a  mea- 
sured quantity  of  the  lettuce-water  is  added  and  the  contents  mixed  by 
shaking.  All  are  allowed  to  stand  for  a  period  varying  from  a  few  minutes 
to  some  hours.  Then  a  small  drop  of  freshly-prepared  tincture  of  guaiao 
is  added  to  each,  mixed  by  shaking,  and  allowed  to  stand  for  one  or  two 
minutes ;  the  glasses  are  then  arranged  in  the  order  of  depth  of  colour. 

In  this  way  it  is  found  that  many  drugs  greatly  lessen  or  almost  com- 
pletely abolish  the  oxidising  power  of  protoplasm,  so  that  while  the  lettuce- 
water  in  the  standard  glass  assumes  a  dark-blue  colour,  that  in  the  others 
exhibits  varying  shades  of  blue,  or  may  even  retain  the  creamy-white 
colour  caused  by  the  guaiac  without  showing  any  blue  whatever. 

The  colour  is  deeper  and  the  reaction  is  more  readily  obtained  when 
the  tincture  of  guaiac  is  mixed  with  some  substance  capable  of  giving  off 
oxygen  readily,  such  as  a  solution  of  peroxide  of  hydrogen  in  ether,  usually 
called  ozonic  ether. 

A  number  of  experiments  made  with  potato-water  by  Cash  and  myself 
showed  that  oxidation  in  potato  solution  was  diminished  most  powerfully  by 
strychnine,,  then  by  quinine  and  coniine;  next  by  morphine,  codeine,  cin- 
chonine,  and  atropine,  each  of  which  had  almost  exactly  the  same  action ; 


70  PHAEMACOLOGY  AND  THEKAPEUTICS.     [sect.  I. 

next  by  nicotine,  and  then  veratrine.  Aconitine  seemed  neither  to  retard 
nor  accelerate  oxidation,  and  presented  exactly  the  same  degree  of  coloration 
as  the  standard  solution.  Caffeine,  picrotoxin,  and  digitalin  appeared  some- 
what to  hasten  oxidation.1 

Reduction  by  Protoplasm. — Ehrlich 2  has  shown,  in  an 
interesting  manner,  the  properties  of  oxidation  and  reduction 
possessed  by  protoplasm.  Methylene-blue,  alizarin-blue,  and 
indo-phenol  are  coloured  bodies  which  become  colourless  on 
being  reduced.  After  injecting  methylene-blue  into  the  veins,  he 
found  that  most  of  the  parenchymatous  tissues  became  coloured, 
the  heart,  brain,  cortex  of  kidney,  the  voluntary  muscles,  &c, 
while  the  lungs  and  the  liver  were  normal  and  only  a  small 
amount  of  colouring  matter  could  be  obtained  by  prolonged 
exposure  to  the  air.  Ehrlich  concluded  that  the  indifferent 
paraplasma  of  the  cells  excretes  the  unchanged  matter,  while 
the  protoplasm,  which  is  greedy  for  oxygen,  excretes  the  reduced 
colouring  stuff. 

Action  of  Drugs  on  Blood. 

The  haemoglobin  of  blood  has  also  the  power  of  taking  up 
oxygen  readily  and  giving  it  freely  off  again.  Haemoglobin  free 
from  oxygen,  or,  as  it  is  sometimes  called,  reduced  haemoglobin, 
is  recognised  by  the  simple  band  which  it  gives  between  D  andE, 
when  examined  spectroscopically. 

Hemoglobin  combined  with  oxygen,  or  oxyhemoglobin,  gives 
two  bands,  situated  in  nearly  the  same  portion  of  the  field  of  the 
spectroscope.  These  are  separated  from  one  another  by  a  clear 
space,  and  are  more  sharply  defined  and  darker  than  the  spec- 
trum of  haemoglobin. 

The  oxygen  of  oxyhemoglobin  may  be  replaced  by  other 
gases.  Thus: — Carbonic  oxide  drives  out  the  oxygen  from 
oxyhaemoglobin  and  forms  carbonic  oxide  haemoglobin  (CO- 
haemoglobin).  This  is  a  comparatively  stable  compound.  It 
presents  spectroscopic  bands  nearly  the  same  as  those  of  oxy- 
haemoglobin, but  which  are  slightly  nearer  to  the  violet  end  of 
the  spectrum.  This  compound,  being  stable,  circulates  in  the 
blood  without  performing  the  functions  of  respiration.  It 
neither  takes  up  oxygen  in  the  lungs  nor  gives  off  oxygen  to  the 
tissues. 

Animals  poisoned  by  CO  therefore  die  of  asphyxia,  the  in- 
ternal respiration  being  arrested,  and  their  blood  remains  for  a 
long  time  of  a  florid  colour. 

Hydrocyanic  acid  appears  also  to  form  a  compound  with 
haemoglobin,  which  is  much  less  stable  than  that  of  carbonic 
oxide.     There  has  been  a  good  deal  of  discussion  about  this 

1  St.  Bartholomew's  Hospital  Reports,  1882. 

2  Ehrlich,  '  Zur  biologischen  Verweitung  des  Methylen-Blau,'  Centralblatt  f. 
die  med.  Wissenscha/t.   1885,  No.  8. 


chap,  in.]    ACTION  OF  DBUGS  ON  PEOTOPLASM,  ETC.      71 

compound,  and  its  existence,  indeed,  has  been  denied.  The 
spectrum  of  this  compound  consists  of  a  single  band  resembling 
reduced  haemoglobin,  but  nearer  the  violet  end  of  the  spectrum. 

Solutions  of  haemoglobin  when  boiled  are  completely  decom- 
posed into  haematin  and  a  proteid  body  or  bodies. 

Haematin  gives  a  single  band,  which  differs  according  as  the 
solution  is  alkaline  or  acid,  and  according  as  the  solvent  is  water 
or  ether. 

Acids  split  up  haemoglobin  into  haematin  and  a  proteid.  It  is 
sometimes  possible  to  get  these  to  recombine  and  to  again  form 
haemoglobin,  but  this  is  far  from  being  always  the  case. 

Methaemoglobin  appears  either  to  be  a  product  of  the  in- 
complete decomposition  of  haemoglobin  or  of  its  excessive  oxida- 
tion. Some  think  that  it  contains  more  oxygen  than  haemoglobin, 
but  less  than  oxyhaemoglobin.  Others  think  that  it  is  a  per- 
oxyhaemogldbin  containing  more  oxygen  than  oxyhaemoglobin. 
At  all  events  the  oxygen  is  more  firmly  combined  in  methaemo- 
globin than  it  is  in  oxyhaemoglobin. 

This  body  is  distinguished  by  a  spectroscopic  band  nearly  in 
the  same  place  as  that  of  the  acid  haematin. 

When  the  solution  is  made  alkaline  by  ammonia  this  band 
disappears,  and  is  replaced  by  another  fine  one  near  D. 

Methaemoglobin  appears  to  be  converted  again  into  haemo- 
globin by  the  action  of  reducing  agents  and  subsequent  oxidation. 
When  its  solution  is  treated- with  reducing  agents,  it  shows  the 
spectrum  of  reduced  haemoglobin  ;  and  on  shaking  this  with  air 
oxyhaemoglobin  is  formed,  as  shown  by  the  appearance  of  its 
characteristic  bands. 

When  blood  is  allowed  to  stand  for  a  length  of  time,  it 
assumes  a  brownish  colour  and  gives  the  bands  of  methaemo- 
globin. When  nitrites  are  mixed  with  freshly-drawn  blood,  they 
impart  to  it  a  chocolate  colour,  and  it  then  exhibits  the  bands  of 
methaemoglobin. 

As  the  oxygen  in  methaemoglobin  is  more  firmly  combined 
with  it  than  in  oxyhaemoglobin,  substances  such  as  the  nitrites 
interfere  with  internal  respiration,  and  thus  in  large  doses  will 
cause  symptoms  of  asphyxia ;  but  their  action  differs  from  that 
of  carbonic  oxide  in  one  very  important  particular,  viz.,  that  it 
is  altered  by  asphyxia;  whilst  that  of  carbonic  oxide  is  not. 
Eeducing  substances  are  constantly  present  in  the  blood  and 
tissues,  and  these  accumulate  to  a  greater  extent  during  the  pro- 
cess of  asphyxia.  Carbonic-oxide  haemoglobin,  being  a  stable 
compound,  remains  unaffected  by  these,  and  the  blood  continues 
to  circulate  unchanged. 

But  methaemoglobin,  which  is  produced  by  the  action  of  the 
nitrites,  becomes  reduced  by  these  substances  and  forms  the 
normal  reduced  haemoglobin  ordinarily  present  in  venous  blood. 
When  this  reaches  the  lungs  it  again  takes  up  oxygen,  forming 


72  PHARMACOLOGY  AND  THEEAPEUTICS.     [sect.  I. 

normal  arterial  blood,  by  which  the  internal  respiration  is  again 
restored.  Thus,  unless  new  supplies  of  nitrites  are  constantly- 
added  to  the  blood,  the  asphyxia  they  occasion  quickly  passes 
away.  That  caused  by  carbonic  oxide,  on  the  contrary,  is  much 
more  permanent.  It  is  not  removed  by  artificial  respiration,  and 
in  order  to  save  the  life  of  the  animal  or  person  poisoned  by  it,  a 
quantity  of  the  poisoned  blood  must  be  withdrawn  from  the  veins 
and  healthy  blood  introduced  by  transfusion. 

Oxyhemoglobin 

Haemoglobin 

Carbonic-oxide      hsemo- 1 
giobin j 

Sulphsemoglobin 

Ditto,  oxygenated 

Methaemoglobin 

Bloodtreatedwithnitrite  ] 
of  amyl  and  alcohol ...  J 

Acid  hrematin  (alcoholic  ] 

solution) J 

Alkaline    hsematin    (al-  ] 

coholic  solution) ) 

Blood       treated       with 

cyanide  of   potassium 

or  hydrocyanic  acid. . . 
Ditto,  oxidised 

C  D  B  5       V 

Fig.  12.— Chart  showing  the  spectroscopic  absorption-bands  of  haemoglobin  and  its  derivatives. 

(After  McMunn.) 

A  method  of  ascertaining  the  effect  of  drugs  on  oxidation  in 
the  blood  consists  in  estimating  the  rate  at  which  acid  is  de- 
veloped in  it  after  its  removal  from  the  body. 

In  this  way  Binz  and  his  scholars,  Zuntz,  Scharrenbroich, 
and  Schulte,  have  found  that  both  quinine  and  sodium  nitro- 
picrate  stop  the  formation  of  acid ;  cinchonine  lessened  it.1 

The  alterations  effected  in  the  interchange  between  blood 
and  the  air  have  also  been  observed  by  simply  allowing  the  blood 
mixed  with  the  drug  to  stand  for  a  certain  time  in  a  closed 
receiver,  partially  filled  with  air,  and  afterwards  analysing  the 
gases  which  the  receiver  contains  at  the  end  of  the  experiment. 

By  this  mode  of  experimentation,  Harley 2  found  that  hydro- 
cyanic acid  diminished  or  arrested  the  processes  of  oxidation 
in  the  blood.  Alcohol,  chloroform,  quinine,  morphine,  nicotine, 
strychnine,  and  brucine,  all  had  a  similar  action,  though  varying 
in  extent,  all  of  them  diminishing  both  the  amount  of  oxygen 
absorbed  and  of  carbonic  acid  given  out. 

Uric  acid  and  snake  poison  had  a  contrary  effect,  increasing 

1  A  very  complete  list  of  the  literature  of  this  subject  is  given  by  Binz  in  his 
work,  Das  Chinin,  Berlin,  1875. 

2  Harley,  Phil.  Trans.,  1805,  p.  678. 


"BHflTT 1 ' ■ 

Sf     9HRnr 

■      I "'" ; 
..       . 

Hi_ H 

III,!.  I      .lil 

EH  II    s 


chap,  in.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.      73 

the  absorption  of  oxygen  and  the  evolution  of  carbonic  acid. 
Curare  appeared  to  lessen  the  absorption  of  oxygen,  but  in- 
creased the  evolution  of  carbonic  acid.  Mercuric  chloride 
lessened  the  •  carbonic  acid,  but  increased  the  absorption  of 
oxygen.  Arsenious  acid  and  tartar  emetic  diminished  the  ab- 
sorption of  oxygen,  but  arsenious  acid  appeared  also  to  lessen 
the  evolution  of  carbonic  acid,  while  tartar  emetic  appeared  to 
increase  it. 

Catalysis. — Fermentation. — Inorganic  Ferments. 

There  are  many  examples  of  chemical  reactions  which  only 
occur  between  two  bodies  when  a  third  is  present,  which  may 
nevertheless  be  found  unchanged  at  the  end  of  the  process. 
Notwithstanding  the  fact  that  the  third  body  is  found  unchanged 
at  the  end  of  the  process,  it  may  have  undergone  changes  during 
the  continuance  of  the  process.  Thus  alcohol  is  not  converted 
into  ether  and  water  by  boiling  alone,  but  it  does  undergo  this 
conversion  by  boiling  with  sulphuric  acid.  The  acid  is  found 
unchanged  at  the  end  of  the  process,  but  is  changed  during  it 
into  ethyl- sulphuric  acid,  which,  combining  with  alcohol,  again 
yields  sulphuric  acid  along  with  ether. 

In  other  cases,  however,  we  cannot  show  that  the  substance 
has  undergone  change.  Thus  starch  is  converted  into  dextrin 
and  sugar  and  cane-sugar  into  grape  sugar  by  boiling  with  acids, 
but  we  do  not  at  present  know  that  the  acid  has  undergone  any 
change  during  the  process  as  it  does  in  the  preparation  of  ether. 
Peroxide  of  hydrogen  is  rapidly  decomposed  by  finely  divided 
platinum  or  silver,  and  finely  divided  platinum  will,  on  the  other 
hand,  cause  oxygen  and  hydrogen  to  unite  rapidly.  Such 
actions,  where  the  third  substance  seems  to  act  by  its  mere  con- 
tact with  the  other  substances,  and  without  undergoing  change 
itself,  are  called  catalytic.  They  are  probably  due  to  an  attrac- 
tion of  some  kind  bordering  both  on  chemical  and  physical 
between  the  molecules. 

Thus  some  organic  substances  would  resist  the  oxidising 
action  of  the  air  for  a  considerable  time,  but  they  are  readily 
oxidised  by  charcoal.  It  is  usually  said  that  the  charcoal  has 
the  power  of  attracting  oxygen  and  condensing  this  gas  upon  its 
surface.  It  does  not  unite  with  the  oxygen  chemically  so  as  to 
form  C02,  but  merely  attracts  it,  holds  it  for  a  while,  and  then 
gives  it  off  readily  to  any  oxidisable  substance.  Platinum, 
palladium,  rhodium,  and  iron  absorb  hydrogen,  palladium  doing 
*  so  to  an  enormous  extent,  especially  when  it  is  in  a  spongy  form. 
The  hydrogen  is  supposed  by  some  to  be  simply  condensed 
within  the  metal,  while  others  think  that  the  hydrogen  and 
metal  unite  to  form  a  hydride.  The  hydrogen  is  given  off  from 
the  metal  in  a  nascent  form,  and  has  very  strong  affinities. 


74  PHAEMACOLOGY  AND   THEEAPEUTICS.     [sect,  i, 

Thus  palladium-hydrogen  readily  reduces  ferric  to  ferrous  salts, 
the  hydrogen  taking  oxygen  from  the  ferric  salt  and  forming 
water.  But  when  the  hydrogen  is  liberated  from  palladium  or 
rhodium  in  presence  of  oxygen,  it  appears  to  convert  the  oxygen 
into  ozone,  and  greatly  increases  its  oxidising  power.  Thus 
palladium-hydrogen  with  oxygen  colours  a  mixture  of  potassium 
iodide  and  starch  paste  blue,  and  oxidises  hemoglobin  to  met- 
haemoglobin  and  ammonia  to  nitric  acid.  Spongy  rhodium,  or 
iridium  saturated  with  hydrogen,  cause  formic  acid  to  be  oxidised 
to  carbonate,  calcium  formate  being  changed  into  calcium  car- 
bonate. Exactly  the  same  action  is  possessed  by  an  organic 
ferment,  and  in  the  conversion  of  the  formic  into  carbonic  acid 
the  ferment  and  the  spongy  rhodium  or  iridium  are  alike  un- 
changed. Spongy  platinum,  palladium,  rhodium,  and  iridium 
may  thus  be  regarded  as  inorganic  ferments.1 

Ferments  Organic  and  Organised. 

The  mechanical  energy  displayed  in  the  movements  of  proto- 
plasm is  supplied  by  processes  of  chemical  change,  and  chiefly  of 
oxidation. 

By  these  processes  some  of  the  substances  contained  in  the 
protoplasm  are  destroyed,  and  their  place  must  be  supplied  by 
fresh  material.  This  material  is  obtained  from  the  food,  but,  in 
order  to  render  it  available  for  the  protoplasm,  its  atoms  must 
be  more  or  less  disintegrated  in  order  that  they  may  again  be 
assimilated.  As  Hermann  very  well  puts  it,  the  bricks  of  which 
the  old  house  is  built  must  be  pulled  asunder  before  they  can  be 


Pig.  13. — An  amoeba  figured  at  two  different  periods  during  movement, 
n,  nucleus  ;  i,  ingested  bacillus. 

built  up  again  into  the  new.  In  the  present  case,  the  bricks 
are  the  atoms  of  protoplasm  in  some  other  organism  living  or 
dead,  which  is  being  used  as  food  by  some  larger  mass  of  proto- 
plasm, as,  for  example,  a  bacillus  which  has  been  absorbed  by 
an  amoeba.     (Fig.  13.)  , 

In  order  to  render  the  protoplasm  in  the  bacillus  available 
for  the  nutrition  of  the  amoeba,  the  atoms  of  which  it  is  composed 

1  Hoppe-Seyler,  Ber.  d.  deutsch.  chem.  Gcscllsck.,  1883,  Feb.  12,  p.  117. 


chap,  in.]    ACTION  OF  DRUGS  ON  PEOTOPLASM,  ETC.      75 

must  be,  to  some  extent,  decomposed.  This  process  appears  to 
be  effected  by  enzymes  or,  as  they  are  sometimes  called,  organic 
ferments. 

Ferments  are  bodies  which  split  up  carbon  compounds  at 
moderate  temperatures  and  lead  to  the  formation  of  other  carbon 
compounds,  most  of  which  are  of  a  simpler  constitution  than  the 
first. 

In  this  definition  we  require  to  introduce  the  term  '  moderate 
temperature,'  because  excessive  heat  alone  will  cause  the  atoms 
of  a  complex  carbon  compound  to  fly  asunder  and  form  simpler 
compounds,  as  in  the  process  of  dry  distillation.  A  less  heat 
than  this,  but  aided  by  the  action  of  powerful  chemicals,  will 
also  produce  the  same  effect.  For  example,  fibrine  heated  with 
diluted  hydrochloric  acid  under  pressure  yields  peptones;  but 
the  same  change  is  effected  at  the  temperature  of  the  mammalian 
body  by  the  aid  of  pepsin.  Trypsin  from  the  pancreas  effects  a 
similar  change  when  mixed  with  water  alone  without  the  aid  of 
an  acid,  though  its  action  is  certainly  aided  by  alkalies.  Neither 
pepsin  nor  trypsin  are  alive,  but  they  contain  carbon,  and  are 
therefore  called  organic  ferments.  But  this  term  easily  leads 
to  confusion  with  ordinary  living  or  organised  ferments,  and  so 
the  term  enzymes  has  been  lately  introduced  to  signify  ferments 
such  as  diastase,  ptyalin,  and  pepsin,  which,  though  they  con- 
tain carbon  and  are  therefore  called  organic,  are  not  alive  and 
have  no  definite  structure,  or,  in  other  words,  are  not  organised. 
The  term  unformed  ferments  has  also  been  applied  to  them. 

By  organised  ferments  we  mean  minute  living  organisms, 
which  in  the  course  of  their  life-processes  cause  decomposition  of 
the  substances  in  which  they  live.  They  have  also  been  called 
formed  ferments.    Examples  of  these  are  yeast  and  bacteria. 

The  processes  of  fermentation  have  been  divided  by  Hoppe- 
Seyler  into  two  kinds : — 

(1)  Those  in  which  water  is  taken  up;  and  (2)  those  in  which 
oxygen  is  transferred  from  the  hydrogen  to  the  carbon  atom. 

The  hydration  in  the  first  case  is  produced  by  the  ferment 
acting  either  (a)  like  a  dilute  mineral  acid  at  a  high  temperature, 
as  in  diastatic  and  invertive  ferments  and  in  the  decomposition 
of  glucosides;  or  (b)  like  caustic  alkalies  at  a  high  tempera- 
ture, as  in  the  splitting  up  of  fats  or  the  decomposition  of  amide 
compounds.  These  processes  of  fermentation  by  hydration  are 
chiefly  carried  on  by  enzymes. 

The  second  class  of  fermentative  changes  by  the  transference 
of  oxygen  from  the  hydrogen  to  the  carbon,  as  in  lactic  and 
alcoholic  fermentation  and  in  putrefactive  processes,  are  chiefly 
produced  through  the  agency  of  organised  ferments.  The  action 
of  the  latter  may  be  to  a  certain  extent  imitated  by  spongy 
platinum,  which  absorbs  oxygen  readily,  and  readily  gives  it  off 
again  to  oxidisable  substances.   Thus  acetic  fermentation  usually 


7C 


PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect,  i. 


produced  by  an  organised  ferment  may  be  also  brought  about  by 
spongy  platinum. 

The  products  formed  by  the  action  of  organised  ferments 
on  the  media  in  which  they  live  are  poisonous,  to  them;  and 
when  these  products  accumulate  above  a  certain  proportion, 
they  kill  the  ferments.  Just  as  a  fire  will  be  smothered  in 
its  own  ashes,  or  an  animal  in  a  confined  space  will  be 
poisoned  by  the  carbonic  acid  which  it  has  itself  produced,  so 
the  yeast  plant,  when  living  in  a  solution  of  sugar,  is  killed  by 
the  alcohol  which  it  produces,  as  soon  as  this  amounts  to  20  per 
cent. ;  and  other  organised  ferments  have  their  lives  limited  in 
a  similar  way. 

Action  of  Drugs  on  Enzymes. — Although,  with  the  ex- 
ception of  a  kind  of  pepsin  in  the  naked  protoplasm  of  JEthalium 
septicum,  a  species  of  myxomycetes,1  enzymes  have  not  been 
shown  to  be  present  in  the  protoplasm  of  the  lowest  organisms, 
it  is  probable  that  the  processes  of  life  in  all  living  beings  from 
the  lowest  to  the  highest  are  carried  on  by  their  means.  A 
ferment,  which  is  evidently  of  the  greatest  importance  in  the 
animal  economy,  has  been  recently  discovered  in  the  blood  by 
Schmiedeberg.  He  has  given  to  it  the  name  of  Histozyme, 
and  he  believes  that  its  function  is  to  split  up  nitrogenous  sub- 
stances preparatory  to  their  oxidation.2  The  chief  enzymes  are 
the  following : — 

I  i  Diastase  from  malt. 

Ptyalin  from  saliva. 

Diastatic  ob  J      amyloids  into  maltose  A  ^?yloPsin  fr°m  P^creas. 
Aklolytic   1  Other  ferments  having  a  similar  action 

.     from  other  parts  of  the  body. 

From  small  intestine. 


Inveksive 

Fekments 


Which  convert  starch  and 
amyloids  into  maltose  . 

Which    convert    maltose 
into  glucose  . 

I  Which  convert  cane  sugar 
into  dextros*  and  levu- 
lose       .        .        .        . 
Which  decompose  gluco- 
sides      .... 
Decomposing  sugar  . 


'  Invertin  from  the  intestinal  juice. 

„  „       mucus  of  the  mouth. 

„  „       tissue  of  the  testis. 

Emulsin  from  bitter  almonds. 
Myrosin  from  mustard. 
.Rennet, 
f  From  stomaoh. 

n 


Proteolytic 

Fekments 


(Which  decompose  proteids 
and  form  peptones 


Decomposing  fats     ,        .  ,  ..,  ,„J  .  . 

1  From  pancreas  (Stearopsin). 

Pepsin  from  stomach. 

Trypsin  from  pancreas. 

Others  from  saliva. 

Histozyme. 

The  action  of  drugs  on  enzymes  is  ascertained  by  taking  two  portions  of 
a  solution  containing  the  enzyme  and  the  substance  to  be  acted  upon.  To 
one  of  these  a  quantity  of  the  drug  to  be  tested  is  added,  the  other  acts  as  a 
standard  with  which  to  compare  it.  If  the  drug  is  in  solution,  a  correspond- 
ing quantity  of  water  must  be  added  to  the  standard  solution  in  order  that 
both  may  be  alike.  _  They  are  then  placed  in  a  warm  chamber  and  the 
rapidity  of  digestion  is  noted. 


1  Krukenberg,  Untersuch.  a.  d.  physiol.  Inst.  d.  Univ.  Heidelberq,  Bd  II    1878, 
p.  273. 

8  Schmiedeberg,  Arch.f.  exyer.  Path.  u.  Pharm.,  Bd.  xiv.  S.  379. 


chap,  in.]    ACTION  OF  DEUGS  ON  PKOTOPLASM,  ETC.      77 

The  effect  of  some  of  the  more  important  drugs  on  the  action 
of  enzymes  will  be  readily  seen  from  the  following  table  from 
Wernitz,  quoted  by  Meyer.1  In  it  the  proportion  is  shown  of 
the  drugs  which  arrest  in  watery  solution  the  action  of  enzymes ; 
thus,  one  part  of  chlorine  in  8,540  parts  of  a  watery  solution  will 
arrest  the  action  of  ptyalin  upon  starch  paste,  while  creasote  has 
.no  action  on  it  even  in  saturated  solution,  and  corrosive  sublimate 
is  so  enormously  destructive  as  to  arrest  its  action,  even  in  one 
part  in  52,000. 

1  Hermann  Meyer,  '  Ueber  das  Milchsaureferment  u.  sein  Vernal  ten  gegen 
Antiseptica,'  Inaug.  Diss.  Dorpat,  1880. 


78 


PHAEMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 


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chap,  hi.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC. 


The  different  action  which  the  same  drug  exerta  upon  formed 
and  unformed  ferments  is  of  great  importance,  because  upon  it 
depends  our  power  to  use  the  drug  in  the  practice  of  medicine. 
Thus  creasote,  which  appears  from  the  preceding  table  not  to 
destroy  the  digestive  power  of  ptyalin  and  to  have  but  a  weak 
action  upon  that  of  pepsin,  has  been  found  by  Werneke  to  destroy 
yeast  in  a  dilution  of  one  part  to  500  of  water ;  and  by  Bucholtz 
to  kill  bacteria  in  a  dilution  of  one  part  to  1,000  of  water.  This 
difference  enables  us  to  arrest  fermentation  in  the  stomach  de- 
pending on  the  presence  of  low  organisms,  while  the  digestive 
action  of  the  pepsin  is  not  interfered  with,  or  only  very  slightly. 
The  following  diagram  shows  the  action  of  drugs  on  enzymes 
and  on  the  lactic  ferment,  which  is  a  bacillus. 


Fig.  14.— Diagram  to  show  the  different  action  of  drags  on  different  enzymes.    The  nature  of  the 
line  showing  the  action  of  each  drug  is  shown  under  its  name. 


80  PHABMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

Zymogens. 

As  several  enzymes  act  readily  in  neutral  or  slightly  alkaline 
fluids,  it  is  evident  that  if  they  existed  free  in  every  part  of  the 
animal  body,  they  would  soon  lead  to  its  speedy  destruction. 
Accordingly,  we  find  that  they  do  not  normally  exist  free,  except 
at  the  times  and  places  they  are  required. 

This  fact  was  first  discovered  by  Kiihne  in  relation  both  to  the  stomach 
and  pancreas,  and  was  announced  by  him  in  the  course  of  lectures  which  he 
delivered  at  Amsterdam  in  1868-69,  which  I  attended.  In  my  note-books  of 
those  lectures  I  find  that  he  stated  that  there  seems  to  exist  '  a  pepsin-giving 
substance,'  because  if  a  '  slice  of  stomach  is  thrown  directly  into  dilute  HC1 
of  4  parts  to  1,000  of  water  at  40°  C.  no  digestion  takes  place,' '  a  fact  which 
shows  that  pepsin  is  not  always  present  in  it.  In  regard  to  the  pancreas,  he 
not  only  recognised  the  existence  of  a  ferment-yielding  body,  but  described  a 
mode  of  obtaining  ferment  from  it  in  the  following  words  : — '  Glands  which 
have  no  action  on  fibrine  can  be  made  active  by  digesting  in  very  dilute  acid 
and  then  neutralising  or  alkalising,  there  seeming  to  exist  a,  ferment-forming 
substance  in  the  pancreas.' 

Kuhne's  discovery  of  the  existence  of  ferment-yielding  bodies  does  not 
seem  to  have  become  widely  known,  and  it  was  again  made  independently  by 
Liversedge  2  in  regard  to  the  amylolytic  ferment  of  the  pancreas,  and  by 
Heidenhain  in  regard  to  trypsin.  These  observers  found  that  when  glands 
which  did  not  contain  ferment  were  exposed  to  the  air  ferments  were  formed. 

Heidenhain3  also  investigated  more  fully  these  ferment- 
forming  substances,  and  gave  to  them  the  name  of  zymogens. 

The  methods  by  which  we  obtain  ferments  from  zymogens 
are,  therefore,  exposure  to  air  and  treatment  with  acids. 


Organised  Ferments. 

The  chief  organised  ferments  are  the  yeast-plant,  which 
produces  alcohol  and  carbonic  acid  from  grape  sugar,  and 
various  kinds  of  bacteria,  one  of  which  produces  butyric, 
another  lactic,  and  another  acetic  fermentation.  Both  yeast  and 
bacteria  belong  to  the  lowest  class  of  plants,  the  protophytes. 
To  this  class  also  belong  moulds,  the  action  of  drugs  upon  which 
is  sometimes  important,  inasmuch  as  moulds  give  rise  to  some 
skin  diseases. 

Yeasts,  moulds,  and  bacteria  have  been  variously  classified 
by  different  authors,  and  the  classification  is  apt  to  undergo 
changes  as  our  knowledge  of  the  life-history  of  these  different 
organisms  increases. 

At  present  it  is  not  certainly  known  whether  the  various 

1  Just  after  this  there  is  unfortunately  a  blank  in  my  notes,  but  Professor 
Kiihne  has  kindly  supplied  the  deficiency,  and  informs  me  that  he  was  then  speak- 
ing of  slices  taken  from  the  external  surface  of  the  stomach,  and  therefore  containing 
the  lower  ends  only  of  the  gastric  glands. 

2  Liversedge  (Nov.  1872),  Journ.  of  Anat.  and  Physiol.,  Nov.  1873,  p.  23. 
•  Heidenhain,  Pflilger's  Archiv,  Bd.  xi.  p.  557. 


chap.  in.].  ACTION  OF  DRUGS  ON  PROTOPLASM,  ETC.      81 

kinds  of  bacteria,  for  example,  are  generically  or  specifically  differ- 
ent, or  whether  they  can,  by  altered  cultivation,  be  transformed 
into  one  another  or  not. 

Koch,  who  has  cultivated  them  by  the  dry  process  on  gelatine 
instead  of  in  liquid,  and  has  thus  been  able  to  avoid  admixture 
of  different  kinds  of  bacteria,  has  come  to  the  conclusion  that 
each  kind  possesses  distinctive  characters ;  but  Klein  has  shown 
that,  even  when  cultivated  in  this  way,  bacteria  may  vary  much 
in  form.  Thus  the  bacillus  anthracis  may  form  torula-like  cells, 
from  which  ordinary  bacilli  are  again  produced, 

The  numerous  names  used  in  treatises  on  the  subject  of 
organised  ferments  are  apt  to  lead  to  confusion,  hence  some  of 
the  names  are  given  here  simply  for  the  purpose  of  reference. 
Thus  Brefeld's  classification  is  : — 

(1)  '  Phycomycetes  =  algoid  fungi ;  (2)  Mycomycetes  =  true 
higher  fungi ;  (3)  Myxomycetes  =  gelatinous  fungi ;  (4)  Blasto,- 
mycetes  =  yeast  fungi ;  (5)  Schizomycetes=bacteria. 

The  classification  into  yeasts,  moulds,  and  bacteria  which  I 
have  followed  may  not  be  botanically  correct,  but  it  is  convenient 
for  our  present  purpose. 

"  Yeasts. — The  yeast-plant,  to  which  various  names  have  been 
given,  as  torula  cerevisiae,  saccharomyces,  consists  of  ovoid  cells, 
which  multiply  by  budding.  The  buds  may  remain  attached, 
forming  torula-chains,  but  when  they  attain  the  size  of  the  parent 
cell  they  fall  off  and  begin  to  multiply  anew.  When  placed  in 
saccharine  solutions  the  plant,  during  the  process  of  growth, 
decomposes  the  sugar  and  forms  alcohol  and  carbonic  acid, 

In  this  process  oxygen  is  usually  absorbed  from  the  air  in 
considerable  quantities,  but  fermentation  can  occur  in  saccharine 
solutions  even  when  oxygen  is  excluded,  though  under  such  con- 
ditions the  torula  grows  slowly.  When  plenty  of  oxygen  is 
present,  and  the  layer  of  fluid  shallow,  the  torula  grows  luxuri- 
antly, but  there  is  very  little  fermentative  change ;  while,  on  the 
other  hand,  when  free  oxygen  is  excluded  the  torula  grows 
slowly,  but  there  is  marked  fermentation. 

Another  plant  nearly  allied  to  yeast  is  the  mycoderma  vini, 
the  ferment  which  changes  alcohol  into  acetic  acid.  The  myco- 
derma is  not  regarded  by  Naegeli  as  a  species  distinct  from 
torula,  and  it  is  considered  by  Grawitz  to  be  the  same  as  the 
fungus  found  in  the  aphthous  patches  which  occur  about  the 
mouth  and  throat  of  children  suffering  from  thrush,  although 
this  fungus  is  usually  said  to  be  an  oi'dium. 

To  teat  the  action  of  drugs  on  alcoholic  fermentation,  equal  quantities  of 
a  solution  of  grape  sugar  with  yeast  are  introduced  into  two  test-tubes,  and 
to  one  of  them  a  little  of  the  substance  to  be  tried  is  added.  These  are  then 
inverted  over  mercury  and  kept  in  a  warm  place  for  several  days.  The 
amount  of  gas  developed  is  then  measured,  and  the  power  of  the  drug  to 
prevent  fermentation  is  estimated  by  the  diminution  in  the  amount  of 
carbonic  acid  produced,  as  compared  with  the  standard. 

a 


'82  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

Mould  Fungi,  or  Hyphomycetes. — These  form  long  fila- 
ments or  hyphse,  which  become  agglomerated  into  a  mycelium 
or  mass  of  compact  tufts.  They  multiply  not  only  by  gemmation, 
but  by  the  formation  of  spores. 

These  moulds  vary  considerably  according  to  the  soil  in 
which  they  grow,  and  the  amount  of  oxygen  present.  Thus,  if 
the  spores  of  the  common  white  mould,  Mucor  mucedo,  are  sown 
in  a  liquid  containing  sugar  and  exposed  to  the  air,  they  grow  on 
the  surface,  forming  branched  hyphss  without  septa,  and  the 
liquid  absorbs  oxygen.  But  if  the  mycelium  be  immersed,  or  the 
oxygen  withdrawn,  septa  develop  in  the  hyphse,  and  they  break 
up  into  segments  which  multiply  by  budding,  forming  a  kind  of 
yeast  with  large  cells,  and,  like  the  true  yeast,  decomposing  sugar 
into  alcohol  and  carbonic  acid. 

They  may  be  trained  to  thrive  on  substances  on  which  they 
do  not  usually  grow  by  gradually  altering  the  composition  of 
the  soil.  Thus,  the  commonest  of  all  moulds,  Penicilliwm 
glaucum,  although  it  does  not  usually  grow  on  blood,  may  be 
trained  to  do  so  by  transplanting  it  from  bread  to  peptone,  and 
then  to  blood. 

Heat  destroys  these  fungi,  but  a  much  higher  temperature  is 
required  to  kill  the  spores  than  the  perfect  plant,  and  in  order  to 
destroy  the  spores  a  temperature  of  110D-115°  C,  kept  up  for 
an  hour,  is  requisite. 

The  mould-fungi  cause  some  local  diseases  in  the  body,  and 
especially  skin  diseases  such  as  favus,  tinea  tonsurans,  tinea 
versicolor,  tinea  sycosis,  onychomycosis,  and  the  madura-foot  or 
fungus-foot  of  India.     They  also  occur  in  the  fur  of  the  tongue. 

Bacteria,  or  Schizomycetes. — Bacteria  are  every  day  be- 
coming more  and  more  important  on  account  of  the  relation  in 
which  they  are  found  to  stand  to  various  diseases.  Anthrax, 
diphtheria,  phthisis,  and  typhoid  fever,  are  probably  all  due  to 
various  species  of  bacteria  introduced  into  the  body,  and  affecting 
various  organs  in  it.  It  is,  therefore,  of  the  greatest  possible 
importance  that  their  life-history  should  be  learned,  and  that  we 
should  know  what  the  conditions  are  under  which  they  thrive 
best,  and  what  the  conditions  are  which  will  destroy  their  life 
and  prevent  their  development. 

_  They  appear  to  increase  in  two  ways  :  first,  by  simple  multi- 
plication of  their  parts,  and  secondly,  by  forming  spores. 

Bacteria  require  water,  organic  matter,  and  salts,  for  then- 
life.  Some  of  them  also  require  the  presence  of  free  oxygen; 
others  do  not;  hence  they  have  been  divided  by  Pasteur  into 
two  classes  :  aerobious  and  anaerobious.  To  the  anaerobious 
bacteria  oxygen  is  not  merely  unnecessary  but  hurtful,  and 
even  the  _  aerobious  bacteria,  although  they  require  oxygen 
in  a  certain  quantity,  are  injured  or  destroyed  by  it  when  it  is 
in  excess. 


chap,  in.]    ACTION  OF  DRUGS  ON  PROTOPLASM,  ETC.      83 


Blastomycetes,  01    ) 
Yeasts  .    / 


Fie.  15. 


(Tornla, 
or  Saccharomyces  (Fig.  151 
01  Mycoderma. 


Hyphomycetes,  or    1 
Moulds    .        .     ) 


Fig.  16. 


/Mucor. 
Penicillium. 
Oldium. 
Achorion. 
Trichophyton 
Microsporcm. 


iWX 


*\\ 


FIG.  17. 


Schizomycetes, 
Bacteria . 


/  Sphaerdbacteria 
(globular  cells) 
Microbacteria,      or 
Bacteria        proper 
(smallj  rod-like  cells) 

Desmobacteria,  or 
Filobacteria  (larger 
rod-like  or  thread- 
like cells) 


1  Micrococcus  (1  (a  &  6)  &  2,  Kg- 16). 
J  Sarcina  (3). 


Bacterium 


Bacillus  (straight) 


Spirobacteria 
(twisted  or   spiral 
cells)       .       .       • 


( Bacterium  termo  (4). 
(B.  llneola(5). 

IB  subtilis(6). 
B.  anthracis  (7). 
B.  septicemia. 
B.  malaria?  (8). 
B.  tuberculosis  (12). 
B.  lepra?. 
Vibrio  (wavy)    .  Vibrio  serpens  (9). 

Spirocha?ta(Iong,flex-  ]  gpirochasta.    Ober- 
ible,      close-wound  f     meyeri(10). 
spirals)    .       .       .  I 
Spirillum  (short,  stiff,  1  s_  T0iutans  (11). 
open  spirals).  .  J 

e  2 


84  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  r. 

The  soil  which  is  most  favourable  to  different  classes  of 
bacteria  varies  with  each  class.  A  struggle  for  existence  goes 
on  between  bacteria  and  other  organised  ferments,  and  between 
different  kinds  of  bacteria  themselves,  in  the  same  way  as  amongst 
higher  plants.  Just  as  an  abundant  crop  of  one  kind  of  higher 
plants  will  occupy  a  whole  field  and  choke  other  plants,  so  that 
kind  of  bacterium  which  grows  most  readily  in  a  particular  soil 
will  choke  others  and  prevent  them  growing  at  the  same  time 
with  itself.  During  their  growth  they  alter  the  soil  or  substance 
in  which  they  grow,  either  by  exhausting  the  nutriment  it 
affords,  or  by  forming  in  it  new  substanaes  which  are  injurious 
to  themselves,  and  thus  they  gradually  die  out. 

But  the  soil  which  is  no  longer  suitable  for  one  kind  of 
bacterium  then  becomes  suitable .  for  another,  and  their  spores, 
which  may  have  lain  without  germinating  during  the  time  the 
first  kind  was  growing,  now  begin  to  grow  actively. 

Thus,  if  a  number  of  germs  of  different  classes  of  fungi  be 
added  at  the  same  time  to  a  saccharine  solution,  the  bacteria 
only  will  grow  and  set  up  lactic  fermentation.  If  a  small  quan- 
tity of  tartaric  acid  be  now  added  (J  per  cent.)  the  yeast  alone 
will  grow  and  alcoholic  fermentation  begins.  If  more  tartaric 
acid  be  added  (4-5  per  cent.)  the  alcoholic  fermentation  stops, 
and  mould  begins  to  grow.  In  this  process  neither  the  bacteria 
nor  the  yeast  are  killed  by  the  addition  of  tartaric  acid,  which,  in 
different  proportions,  merely  renders  the  liquid  more  favourable 
for  the  growth  of  the  yeast  and  mould  respectively,  and  enables 
them  to  flourish  best,,  although  the  others  are  still  present. 

In  fresh  grape-juice  many  germs  are  present,  but  the  compo- 
sition of  the  liquid  being  more  favourable  to  the  growth  of.  the 
yeast-plant  than  to  other  fungi,  it  alone  grows.  When  it  has 
converted  the  sugar  into  alcohol  its  growth  stops,  and  bacteria 
may  then  multiply  and  convert  the  alcohol  into  acetic  acid. 
This  in  turn  checks  the  growth  of  the  bacteria,  and  mould-fungi 
then  find  the  soil  favourable.  In  their  growth  they  consume  the 
lactic  acid,  and  the  liquid  once  more  affords  a  favourable  soil  for 
bacteria,  which  may  then  grow  and  cause  putrefaction. 

The  same  struggle  for  existence  occurs  between  the  different 
species  of  bacteria  themselves.  Thus  micrococci  may  be  pre- 
vented from  growing  by  micro-bacteria,  and  bacilli  may  be  killed 
by  bacterium  termo  when  the  supply  of  oxygen  is  insufficient  for 
both.1 

It  is  to  be  noted,  however,  that  in  the  struggle  for  existence 
the  formation  of  poisonous  products  by  bacteria-  may  be,  and 
probably  is,  beneficial  to  them.  No  doubt  these  poisonous 
products  check  their  own  growth  and  finally  destroy  them ;  but 

1  Ziegler's  Pathological  Anatomy,  translated  and  edited  by  MacAlister,  p.  272. 
This  work  contains  a  very  lucid  and  complete  account  of  disease  germs. 


chap,  in.]  ,  ACTION.  OF  DRUGS  ON  PROTOPLASM,  ETC.      85 

in  the  struggle  for  existence  between  bacteria  and  living  tissues 
these  poisons  may  be  beneficial  to  the  bacteria  by  killing  the 
tissues,  and  thus  giving  the  bacteria  a  more  ample  supply  of 
nutriment. 

In  investigating  any  problem  it  is  always  best  to  take  the 
simplest  case,  and  if  we  look  at  the  struggle  for  existence 
between  bacilli  and  an  amoeba,  or  white  blood-corpuscle,  we  shall 
see  that  the  formation  of  poisonous  products  by  the  bacteria  may 
enable  them  to  destroy  the  amoeba  or  leucocyte  instead  of  their 
being  destroyed  by  it  (Fig.  25,  p.  87). 

These  poisonous  products  in  fact  may  prepare  the  soil  for 
bacteria,  and  this  supposition  is  confirmed  by  the  observations 
of  Eossbach  and  Eosenberger.  Eossbach  found  that  when  papain 
was  injected  into  the  vessels,  micrococci  developed  in  the  blood 
with  extraordinary  rapidity,  the  ferment  seeming  to  have  altered 
the  blood  to  such  an  extent  that  it  became  an  exceptionally 
favourable  soil  for  the  micrococci.  A  similar  result  was  observed 
by  Eosenberger  from  the  injection  of  sterilised  septic  blood.  In 
tbis  blood  the  bacteria  themselves  were  destroyed,  but  the 
poisonous  substances  which  they  had  formed  were  present,  and 
these  seemed  to  have  a  similar  action  to  the  papain. 

The  struggle  for  existence  between  the  Organism  and 
the  Microbes  which  invade  it.— This  has  been  found  by 
Metschnikoff  to  occur  both  in  the  blood  and  the  tissues.  In  the 
daphne,  or  water-flea,  where  the  tissues  are  transparent,  he  has 
been  able  to  observe  the  spores  of  a  kind  of  yeast  passing  from 
the  intestinal  canal  into  the  body-cavity  (Figs.  18,  19).  As  they 
pass  through  they  are  attacked  by  leucocytes — sometimes  by  one, 
sometimes  by  many.  These  leucocytes  occasionally  coalesce 
so  as  to  form  a  Plasmodium.  When  they  are  sufficiently  power- 
ful they  digest  and  destroy  the  spores  (Figs.  19,  20,  and  21). 
Sometimes  the  spores  may  be  left  sufficiently  long  intact  to 
germinate  and  give  off  buds,  which  become  free  in  the  body- 
cavity,  and  may  also,  like  the  parent  spores,  be  attacked  and 
digested  by  leucocytes. 

When  there  are  many  spores  they  destroy  the  leucocytes 
instead  of  being  destroyed  by  them  (Fig.  25). 

The  connective-tissue  cells  also  take  up  and  destroy  the 
microbes,  and,  from  the  property  the  cells  possess  of  eating  up 
the  microbes,  Metschnikoff  names  them  phagocytes.1  He  finds 
that  bacillus  anthracis  is  eaten  up  in  a  similar  way  by  white 
blood-corpuscles  ; 2  and  Fodor 3  has  observed  that  various  kinds  of 
bacteria,  viz.  bacterium  termo,  bacillus  subtilis,  and  bacterium 
megatherium,  as  well  as  the  spores  of  the  latter,  disappear  in 
four  hours  after  they  are  injected  into  the  blood  of  living  rabbits; 

1  Virchow's  ArcMv,  vol.  xcvi.,  p.  177.  z  Idem,  vol.  xcvii.,  p.  502. 

»  Arch,  far  Hygiene,  Bd.  34,  p.  129. 


86 


PHAEMAOOLOGY  AND  THEEAPEUTIOS.     [sect.  i. 


Pig.  18.— A  piece  of  the  anterior  part  of  the  body  of  a  Daphne,  with  a  number  of  spores,  some  of 
which  are  still  in  the  intestinal  canal,  others  are  penetrating  the  intestinal  wall,  and  others 
are  free  in  the  abdominal  cavity,  where  they  are  attacked  by  leucocytes. 


Pw.  19. 

1.  A  spore  which  has  penetrated  the  intestinal  wall  and  entered  the  abdominal  cavity,  where  font 

leucocytes  have  surrounded  its  end.  m,  the  muscular  layer  of  the  intestine  ;  e,  epithelial  layer ;  *, 
the  serous  layer. 

2.  A  spore  surrounded  by  leucocytes  from  the  abdominal  cavity  of  a  Daphne. 

3.  Confluent  leucocytes  enveloping  a  spore. 

4.  A  spore,  of  which  one  end  is  being  digested  by  a  leucocyte. 


Fig.  20.— Different  stages  of  the  changes  undergone  by  spores  through  the  action  of  phagocytes. 


Pia.  21.— A  germinating  spore  with  leucocyte  adherent  to  It, 


chap.  iij.J    ACTION  OF  DKUGS  ON  PEOTOPLASM,  ETC.      87 


/"* 


Fig,  22.— A  spore  germinating  and  forming  conidia,  which  drop  ofE  and  become  free  la 
the  abdominal  cavity. 


Fig.  23.— (i  and  6,  two  stages  in  the  process  of  Fig.  24.— A  leucocyte  enclosing  conidla. 

leucocyte  eating  up  two  conidia. 


Flo.  26.— A  group  of  conidia  which  have  caused  the  leucocytes  surrounding  a  spore  to  dissolve, 
leaving  only  an  empty  vesicle  and  fine  detritus. 


Fig.  26.— A  connective-tissue  phagocyte,  containing  three  fungi-cells. 


Fig.  27.— Leucocyte  of  a  frog  from  the  neighbourhood  of  a  piece  of  the  lung  of  a  mouse  infected  with 
antnrax  about  forty-two  hours  after  the  piece  of  lung  had  been  placed  under  the  skin  of  the 
frog's  back.    The  leucocyte  is  in  the  act  of  eating  up  an  anthrax  bacillus. 


Fig.  28.— The  same  leucocyte,  a  few  minutes  later,  after  It  has  completely  enveloped  the  baoillnv 


88  PHARMACOLOGY  AND  THERAPEUTICS,     [sept.  i« 

but  if  the  animals  are  weak,  or  depressed  by  hunger  or  cold, 
they  have  much  less  power  of  destroying  the  foreign  organisms, 
and  so  a  longer  time  elapses  before  the  bacteria  disappear. 

When  only  a  small  number  of  pathogenic  bacteria,  such  as 
the  bacillus  anthracis,  is  injected  into  the  blood  at  once,  they 
are  destroyed  in  the  organism;  but  when  they  are  in  larger 
numbers,  they  have  the  best  of  the  struggle,  and  the  organism 
itself  is  destroyed.  It  is  probable  that  bacteria  are  constantly 
entering  the  organisms  of  men  and  animals  from  the  lungs  and 
digestive  canal,  but  unless  they  are  excessive  in  number,  and 
virulent  in  their  nature,  they  are  quickly  destroyed.1 

The  septic  poisoning  which  occurs  from  wounds  is  not  due 
merely  to  bacteria  entering  the  blood  from  them,  but  is  due 
chiefly  to  the  absorption  of  the  poisons  which  the  bacteria 
have  formed  in  the  wound.  The  dead  or  enfeebled  tissues 
which  occur  in  the  wound  afford  a  soil  favourable  to  the  growth 
of  the  bacteria,  and  for  the  formation  of  their  deadly  products. 
When  these  are  absorbed  they  not  only  poison  the  tissues 
generally,  but,  by  doing  so,  convert  the  whole  body  into  a  soil 
suitable  for  the  growth  and  development  of  bacteria,  as  is  shown 
by  the  fact  that  the  tissues  of  animals  killed  by  the  injection  of 
sepsin  decompose  very  quickly,  and  swarm  with  bacteria  shortly 
after  death. 

Action  of  Drugs  on  the  Movements  of  Bacteria. 

Mode  of  Experimenting-. — In  order  to  test  the  effect  of  a  drug  on 
the  movements  of  bacteria  already  developed,  a  drop  of  the  solution  contain- 
ing bacteria  may  be  mixed,  under  the  microscope,  .with  a  drop  of  the  solution 
of  a  drug  in  the  way  already  described  at  page  63,  and  the  strength  of 
solution  necessary  to  destroy  their  movements  estimated  in  the  same  manner. 

In  order  to  combine  experiments  on  the  movements,  and  on  the  reproduc- 
tion, so  as  to  ascertain  whether  the  bacteria  which  have  been  rendered 
motionless  by  heat  or  drugs  are  really  dead,  or  are  only  torpid,  the  covering- 
glass  in  the  experiment  just  described  is  taken  up  with  a  pair  of  sterilised 
forceps,  and  dropped  into  some  sterilised  Cohn's  solution  (vide  p.  72).  It  i3 
then  put  along  with  the  standard  solution  into  a  warm  chamber,  and  left  for 
a  day  or  two.  If  the  bacteria  have  been  destroyed,  it  will  remain  clear  like 
the  standard  solution,  but  if  they  have  only  become  torpid,  it  will  be  more  or 
less  opalescent  or  milky. 

In  performing  this  experiment,  great  care  must  be  taken  that  the  solution 
of  the  drug  has  been  sterilised  by  boiling ;  and  that  the  covering-glass,  glass 
slide,  all  the  instruments,  and  indeed  everything  used  in  the  experiments, 
have  been  also  thoroughly  sterilised  by  heating. 

A  temperature  of  66°  to  70°  0.  usually  arrests  the  move- 
ments of  bacteria,  and  if  continued  for  an  hour  destroys  adult 
organisms,  though  not  the  spores.  A  temperature  of  100°  C. 
usually  destroys  the  spores  as  well,  but  this  is  not  always  the  case. 

If  the  bacteria  are  moist,  this  temperature  generally  kills 
them,  but  not  if  they  happen  to  be  dry,  and  a  much  higher  tem- 

1  Fodor,  op.  cifc.  p.  147. 


chap,  in.]    ACTION  OP  DEUGS  ON  PROTOPLASM,  ETC.      89 

perature  is  then  required.  They  may  become  dry,  before  being 
killed,  by  a  little  solution  containing  them  having  flowed  or 
spurted  into  the  higher  part  of  the  tube  or  flask,  where  the  water 
evaporates  and  leaves  them  dry  before  the  temperature  has  been, 
sufficiently  raised  to  destroy  them. 

The  bacteria  grown  in  different  fluids  are  not  all  equally 
sensitive  to  drugs. 

The  most  destructive  substances  to  bacteria  are  corrosive  sub- 
limate, chlorine,  bromine,  and  iodine.  Quinine  and  the  other 
cinchona  alkaloids  also  destroy  bacteria,  their  power  diminishing' 
in  the  following  order :— quinine,  quinidine,  cinchonidine,  and; 
lastly  cinchonine. 

Bebeerine  is  nearly  as  powerful,  and  potassium  picrate  is  even 
superior  to  quinine  when  used  with  Conn's  solution.  When 
bacteria  are  cultivated  in  beef-tea  instead  of  Cohn's  solution, 
potassium  picrate  is  less  powerful. 

Sulphocarbolates  and  strychnine  have  considerable  power, 
though  a  good  deal  less  than  quinine ;  berberin  and  assculin  have 
hardly  any  power  to  destroy  bacteria  at  all.  Sodium  hyposulphite 
has  very  little  action ;  sodium  sulphate  has  a  destructive  action, 
but  is  about  ten  times  less  strong  than  quinine.1 


Action  of  Drugs  on  the  Reproduction  of  Bacteria  in 

general. 

The  spores  of  bacteria  have  an  enormous  power  of  resisting 
agents  destructive  to  their  vitality,  very  much  greater  than  that 
of  the  fully-developed  bacteria.  Thus  it  happens  that  a  quantity 
of,  an  antiseptic,  which  is  quite  sufficient  not  only  to  prevent  the 
spores  of  bacteria  from  developing  so  long  as  they  remain  in  it, 
but  to  destroy  fully-formed  bacteria,  will  not  destroy  the  vitality 
of  the  spores  or  hinder  them  from  germinating  as  soon  as  they 
are  removed  from  the  influence  of  the  antiseptic  and  transferred 
to  a  proper  soil.  < 

Yet  the  power  to  destroy  the  vitality  of  the  spores  completely 
is  what  is  required  in  an  antiseptic,  for  we  wish  to  destroy  the 
infectious  material,  and  prevent  it  from  causing  disease,  rather 
than  to  administer  substances  to  an  animal  which  will  hinder 
the  germs  from  developing  in  the  blood  after  their  introduction 
into  it ;  although  this  may  be  desirable  when  infection  has 
already  taken  place. 

It  is  therefore  necessary  to  test  the  effect  of  drugs  in  destroy- 
ing the  germs  completely. 

Method  of  Experimenting. — This  is  done  by  adding  to  a  fluid,  con- 
taining bacteria  and  their  spores,  varying  quantities  of  an  antiseptic,  and 
allowing  the  mixture  to  stand  for  a  longer  or  shorter  time.    A  drop  jf  this 

1  Buchanan  Baxter,  Practitioner,  vol.  i.  pp.  343,  350. 


90  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

fluid  is  then  introduced  by  a  sterilised  platinum  wire  or  glass  pipette  into 
some  sterilised  Cohn's  fluid  or  beef-tea.  This  is  -watched,  to  see  whether 
bacteria  will  develop  in  it  or  not.  If  they  do  develop,  it  is  clear  that  the 
spores  have  not  been  killed  by  the  admixture  with  the  disinfectant  in  the 
original  fluid ;  if  they  do  riot  develop,  then  the  disinfectant  has  been  sufficiently 
powerful  to  destroy  them. 

The  plan  usually  employed  is  to  take  a  number  of  test-tubes,  plug  their 
orifices  with  cotton-wool,  and  destroy  any  germs  that  may  be  attached  to 
them  by  thoroughly  heating  them  to  about  300°  P.  in  a  hot  chamber,  or  in 
the  flame  of  a  Bunsen's  lamp.  They  are  then  allowed  to  cool,  and  a  small 
quantity  of  a  liquid  (about  5  cc.)  in  which  bacteria  readily  grow  is  placed  in 
each.  This  also  must  be  previously  thoroughly  boiled,  in  order  to  destroy 
any  germs  which  may  be  present  in  it.  The  liquid  recommended  by  Cohn 
consists  of  ammonium  tartrate  one  gramme,  potassium  phosphate  and 
magnesium  sulphate  of  each  five  grammes,  calcium  phosphate  "05  gramme, 
distilled  water  100  cc.  This  is  filtered  and  boiled  before  use.  To  the  tubes 
the  different  agents  to  be  tested  are  added,  the  solutions  of  each  having  been 
carefully  sterilised  by  boiling,  and  the  pipette  used  being  superheated  in  each 
case  before  it  is  employed.  If  the  drugs  are  added  in  solution,  a  similar 
quantity  of  boiled  water  must  be  added  to  the  first  tube,  which  is  to  serve  as 
a  standard.  To  each  of  them  is  then  added  a  single  drop  of  a  liquid  contain- 
ing bacteria. 

The  mouths  of  the  tubes  are  then  stopped  with  the  cotton- wool  and  placed 
for  a  few  days  in  a  warm  chamber  at  about  40°  C.  The  standard  liquid  will 
then  be  found  to  be  opalescent  or  milky.  The'  degree  of  the  opalescence  in 
the  other  tubes  will  be  less  according  to  the  effect  of  the  drug  which  has 
been  added,  in  preventing  the  development  of  bacteria. 

Where  it  has  completely  hindered  the  development,  the  solution  will 
remain  quite  clear,  and  as  its  strength  diminishes,  the  opalescence  will  become 
greater  until  it  is  equal  to  that  of  the  standard. 

In  performing  this  experiment  it  is  best  to  use  one  definite  form  of  bac- 
terium, instead  of  a  mixture  of  several  unknown  kinds.  This  is  referred  to 
again  in  speaking  of  the  experiments  of  Dr.  Koch,  who  generally  employs 
the  micrococcus  prodigiosus  as  an  example  of  an  organism  easily  acted  upon, 
and  the  spores  of  bacillus  anthracis,  or  of  a  bacillus  found  in  earth,  as 
examples  of  resistant  organisms. 

It  is  found  by  this  mode  of  experiment  that  a  smaller  quantity 
of  poison  will  prevent  the  development  of  bacteria  than  will 
destroy  them  after  they  are  developed. 

By  experiments  on  the  comparative  action  of  different  drugs 
on  bacteria  the  results  contained  in  the  following  table  have  been 
obtained  by  N.  de  la  Croix,  and  these  have  been  to  a  considerable 
extent  confirmed  by  Koch. 

It  will  be  seen  by  looking  at  the  table  that  the  exact  limit  of 
the  power  of  each  drug  to  destroy  bacteria  is  not  determined, 
but  that  two  concentrations  of  each  antiseptic  are  given,  one  of 
which  is  sufficient  to  do  it,  and  the  other  is  insufficient.  The 
disinfecting  limit  therefore  lies  between  the  two  experiments. 
But  the  limit  of  disinfection  is  not  an  invariable  one  for  each 
'drug,  as  its  power  to  destroy  bacteria  is  modified  not  only  by  the 
concentration  of  the  solution  employed,  but  by  the  length  of  time 
during  which  it  acts,  and  by  the  temperature. 


chap,  in.]    ACTION  OP  DRUGS  ON  PROTOPLASM,  ETC.      91 


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8)2  PHAKMACOLOGY  AND  THEEAPEUTICS.     [sect.  i„ 


Action  of  Drugs  on  particular  species  of  Bacilli. 

In  these  experiments  of  De  la  Croix,  however,  the  nature  of 
the  bacteria  experimented  on  was  not  determined,  and  there 
might  be  a  mixture  of  several  sorts.  Koch  has  therefore  sought 
to  ascertain  the  action  of  disinfectants  upon  definite  forms  of 
microzymes  by  cultivating  them  in  pure  crops  before  applying 
the  disinfectant.  Those  which  he  has  chiefly  experimented  on 
are  the  red  micrococcus  prodigiosus,  the  bacteria  of  blue  pus,  and 
the  bacillus  anthracis. 

The  first  two  do  not  form  spores,  and  are  easily  destroyed 
by  disinfectants.  The  bacillus  anthracis  forms  spores,  and  was 
therefore  employed  to  test  the  action  of  disinfectants  upon  them. 

mode  of  Experimenting-  on  the  Action  of  Drugs  on  Reproduction 
of  Bacilli. — In  order  to  avoid  admixture  with  other  species,  Koch  culti- 
vated the  first  two  on  slices  of  potato,  instead  of  in  a  solution.  Upon  one 
piece  of  potato  the  unaltered  microzymes  were  sown  (control  specimen),  and 
upon  the  others  similar  microzymes  which  had  been  exposed  to  the  action  of 
disinfectants.  If  the  microzymes  had  been  destroyed  by  the  disinfectants, 
no  result  occurred,  but  if  not,  then  a  crop  was  obtained  which,  in  comparison 
with  the  control  specimen,  was  more  or  less  abundant,  according  as  the  action 
of  the  disinfectant  had  been  less  or  more  complete. 

For  the  cultivation  of  the  anthrax  bacillus,  Koch  used  as  a  soil  gelatine 
mixed  with  some  other  nutritive  substance,  usually  meat  infusion  and  peptone 
sterilised  and  spread  upon  a  slip  of  purified  glass,  and  exposed  to  such  a  heat 
as  just  to  solidify  it.  Koch  did  not  use  his  solidified  blood-serum  in  these 
experiments.  This  could  be  placed  under  the  microscope,  and  the  growth  of 
bacilli  observed  from  day  to  day.  Middle-sized  test-tubes  were  then  par- 
tially filled  with  the  disinfecting  solutions,  and  silk  threads,  steeped  in  a 
fluid  containing  bacilli  and  then  dried,  were  placed  in  them  ;  from  time  to 
time  a  thread  was  removed  from  the  tubes  by  means  of  a  previously  heated 
platinum  wire  arid  placed  on  the  slide,  which  was  then  subjected  to  micro- 
scopical observation.  In  this  way  it  was  easy  to  determine  what  strength  of 
solution,  and  what  time  of  exposure  to  its  action,  were  required  to  destroy  the 
spores. 

The  results  of  experiments  made  in  this  way  with  carbolic 
acid  were  very  surprising.  It  was  to  be  expected  that  carbolic 
acid  would  readily  destroy  the  spores,  but  this  was  not  the  case. 
A  1  per  cent,  watery  solution  had  almost  no  action  upon  them 
even  after  they  had  been  exposed  to  it  for  15  days ;  2  per  cent, 
slightly  retarded  their  growth,  but  it  did  nothing  more ;  3  per 
cent,  killed  the  spores  in  7  days ;  4  per  cent,  in  3  days ;  and  5 
per  cent,  in  1  day. 

This  comparatively  slight  action  of  carbolic  acid  on  spores 
and  the  long  time  that  it  requires  to,  destroy  them  show  that  it 
cannot  be  relied  upon  as  a  universal  disinfectant.  But  it  has 
nevertheless  great  power  in  destroying  microzymes  which  have 
not  formed  spores. 

The  fresh  blood  of  an  animal  which  has  died  from  anthrax' 
contains  only  bacilli  and  no  spores.  When  it  is  mixed  with  its 
own  bulk  of  a  1  per  cent,  solution  of  carbolic  acid,  it  can  very 


<3hap.  in.]    ACTION  OF  DEUGS'ON  PEOTOPLASM,  ETC. 


98 


soon  afterwards  be  injected  into  an  animal  without  producing 
any  marked  symptoms.  A  |  per  cent,  solution  will  not  do  this, 
so  that  the  limit  lies  between  *5  and  -25  per  cent,  of  the  mixture 
(v.  p.  97). 

The  action  of  carbolic  acid  on  other  fully-developed  microzymes, 
or  on  the  spores,  is  almost  j;he  .same  as  on  the  anthrax  bacilli. 

The  following  table  gives  the  result  of  Koch's  experiments 
with  other  substances,  the  figures  indicating  the  number  of 
days  during  which  the  spores  had  been  submitted  to  the  action 
of  the  antiseptic  previous  to  cultivation.  The  black- faced  figures 
indicate  that  the  spores  were  destroyed,  and  their  germination 
prevented  by  exposure  to  the  disinfectant  for  that  number  of 
days ;  a  *  indicates  that  their  vitality  was  diminished,  and  that 
the  crop  from  them  was  scanty ;  a  f  indicates  that  their  growth 
was  retarded;  *t  that  it  was  .both  scanty  and  retarded.  The 
disinfectants  are  divided  into  three  groups.  The  first  contains 
the  group  of  fluids ;  the  second  of  solutions  in  water ;  and  the 
;  third  of  solutions  in  alcohol,  ether,  or  oil. 


Geoup  I.^FLUIDS. 


.  Distilled  water   . 

.Alcohol  (absolute) 

'  Alcohol  (1  to  1  of  water) 

Alcohol  (1  to  2  of  water) 

Ether 

Acetone 

Glycerine   . 

Butyric  acid 

French  salad  oil 

Bisulphide  of  carbon  . 

Chloroform 

Benzol 

Petroleum  ether 
^'Turpentine  oil    . 


7    15    20    35    90 

1      3      5    10-  12    20     30    40    50    65     110 

3    20    30    40    50    65  110 

3    20    30    40    50    65  110 
8*  30 


10    20    30    40    50    65  110 


5 
5' 
3 
5 
30    90 
5     10    20 
3     10    20.100 
5    10    20. 
5 


1*    5    10 


Group  II.— SOLUTIONS  IN  WATEE. 


Chlorine  water  (freshly  made)  . 
Bromine  (2  p.  c.  in  water) 
Iodine  water  (1  in  7,000)  . 
Hydrochloric  acid  (2  p.  c.  in  water) 
Ammonia  .... 

:  Ammonium  chloride  (5  p.  c.  in  water) 
Common  salt  (saturated  solution) 
Calcium  chloride  (saturated  solution), 

'  Barium  chloride  (5  p.  c.  in  water) 
Ferric  chloride  (5.  p.  c.  in  water) 
Potassium  bromiie  (5  p.  c.  in  water) 
Potassium  iodide  (5  p.  c.  in  water) 
Corrosive  sublimate  (1  p.  c.  in  water) 
Arsenic  (1  p.  c.  in  water)  . 

,  Lime  water 

Chloride  of  lime  (5  p.  c.  in  water) 
Sulphuric  aeid  (1  p.  c.  in  water) 

•  Zinc  sulphate  (5  p.  c.  in  water) 
Copper  sulphate  (5  p.  c.  in  water) 
Ferrous  sulphate  (5  p.  c.  in  water) 
Sulphate  of  aluminium  (5  p.  o.  in.water) 


1 
1 
1 

1 
1 
1 
1 
1 
5 

at 

5 
5 
1 
1 
o 

It 

1 

1 

1 

2 

1 


5 

5 

5 
10 

6 
10 
10 

2 

6 
10 

2*t 

3 

5* 

5* 

6 

5 


10 

10 
10 
10 

20 
45 

25 
25 

10 

15* 
5 
10* 
10* 
10* 

12- 


25 
20 

40 
100 


80 


20*t 
20* 


94 


PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


Alum  (4  p.  e.  in  water)      .    _    .        . 
Potassium  chromate  (5  p.  e.  in  water) 
Potassium  bichromate  (5  p.  o.  in  water) 
Chrome  alum  (5  p.  c.  in  water) 
Chromic  acid  (1  p.  a.  in  water)      _    . 
Potassium  permanganate  (5  p.  c.  in  water) 
Do.  do.  (1  p.  o.  in  water) 

Potassium  chlorate  (5  p.  c.  in  water) 
Osmic  acid  (1  p.  c.  in  water)      .        •     _  . 
Boracic  acid  (5  p.  c.  in  water)  not  quite  dissolved 
Boras  (S  p.  c.  in  water)     . 
Sulphuretted  hydrogen  water    . 
Ammonium  sulphide 
Oil  of  mustard  with  water 
Formic  acid  (sp.  gr.  1-120) 
Acetic  acid  (5  p.  c.  in  water)     .     _  . 
Potassium  acetate  (saturated  solution) 
lead  aoetate  (5  p.  c.  in  water)  . 
Soft  (potash)  soap  (2  p.  c.  in  water)  . 
Lactic  acid  (5  p.  c.  in  water)     . 
Tannin  (5  p.  c.  in  water)  . 
Trimethylamine  (5  p.  c.  in  water)     . 
Chloropicrin  (5  p.  c.  in  water)   .  _     . 
Benzoic  acid  (saturated  solution  in  water 
Benzoate  of  sodium  (5  p.  u.  in  water) 
Cinnamio  acid  (2  p.  c.  in  water  60  and  alcohol 

40  parts)      .... 
Indol  (in  excess  in  water) . 
Skatol  (in  excess  in  water) 
Leucin  (A  p.  c.  in  water)    . 
Quinine  (2  p.  c.  in  water  and  40  alcohol  60  parts) 
Quinine  (1  p.  c.  in  water  with  HC1)  . 

Gboot  III— SOLUTIONS  IN  ALCOHOL 

Iodine  (1  p.  e.  in  alcohol) 

Valerianic  acid  (5  p.  c.  in  ether) 

Palmitic  acid  (5  p.  c.  in  ether)  . 

Stearic  acid  (5  p.  c.  in  ether)     . 

Oleic  acid  (5  p.  c.  in  ether) 

Xylol  (5  p.  c.  in  alcohol)    . 

Thymol  (5  p.  c.  in  alcohol) 

Salicylic  acid  (5  p.  c.  in  alcohol) 

Salicylic  acid  (2  p.  c.  in  oil)      .... 

Oleum  animale  (Dippel's  oil,  5  p.  o.  in  alcohol) 

Oleum  menthse  piperita  (5  p.  c.  in  alcohol) 

From  this  table  it  appears  that  the  ordinary  method  of  sepa- 
rating between  formed  and  unformed  ferments  by  precipitation 
with  alcohol  and  solution  in  glycerine  cannot  be  relied  upon  as  a 
trustworthy  means  of  separating  them,  since  neither  alcohol  nor 
glycerine  destroys  the  activity  of  formed  ferments. 

It  is  remarkable  that  ether  and  turpentine  oil,  which  are  both 
ozone  carriers,  should  have  such  a  marked  action  in  comparison 
with  other  fluids.  This  is  in  harmony  with  some  recent  observa- 
tions of  Paul  Bert  and  Eegnard,  who  found  that  oxygenated  water 
in  sufficient  quantity  destroys  the  bacteria  of  anthrax. 

The  spores  of  anthrax  bacilli  resist  in  an  extraordinary  way 
the  action  of  certain  substances  which  usually  are  fatal  to  life,  as 
hydrochloric  acid  (2  per  cent.),  salicylic  acid  (1  per  cent.),  cgp 


1          5 
1         2 

12 

1          2 

1          2 

1          2 

1          2 

2          6 

1          2 

6t 

10f 

5        10 

15 

1          5* 

1          2 

5 

1          5 

10* 

1          2 

4 

10 

1          5 

1         4 

10 

1          5 

12 

1         5 

12 

1          2 

5 

1         6 

10 

1         5 

12 

1         2 

6 

12 

1          5 

10 

45 

90 

1         2 

5 

10 

1         3 

5 

10 

1          5 

10 

25 

80 

1          5 

10 

25 

80 

1         5 

10 

l*t      5*t 

1         5 

10 

j,  OB  BTHEE,  OB  OIL. 

1*        2* 

1          5 

1          5 

1          5 

1          5 

1          5 

30 

60 

90 

1          6 

10 

15 

1          6 

10 

15 

5        10 

20 

80 

1      v  "5 

12 

1          5 

12 

chap,  in.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.      95 


centrated  solutions  of  chloride  of  sodium,  chloride  of  calcium, 
metallic  solutions,  borax,  boric  acid,  chloride  of  potassium, 
benzoic  acid,  benzoate  of  sodium,  cinnamic  acid,  and  quinine. 

Action  of  Drugs    on  the    Development    and    Growth  of  Bacilli. — 

In  order  to  test  the  action  of  disinfectants  on  the  development  and  growth 
of  bacteria,  Koch  put  into  a  number  of  small  watch-glasses,  or  rather 
crystallisation-glasses  with  flat  bottoms,  a  few  drops  of  blood-serum,  or  a 
solution  of  extract  of  meat  and  peptone,  mixed  with  varying  quantities  of 
the  disinfectant.  Into  each  of  these  a  silk  thread,  which  had  been  dipped 
in  the  fluid  containing  bacteria  and  dried,  was  placed.  In  one  glass  serum 
alone,  without  any  disinfectant,  was  placed,  in  order  to  ascertain,  by  com- 
parison with  the  growth  which  takes  place  in  it,  how  the  disinfectant  in  the 
other  glasses  had  interfered  with  the  growth  of  the  bacilli. 

In  experiments  of  this  sort  a  difference  was  found  between 
anthrax  bacilli  and  other  microzymes.  A  dilution  of  carbolic 
acid,  1  in  1,250  and  1  in  850,  sufficed  to  prevent  the  growth  of 
anthrax  bacilli,  while  a  strength  of  1  in  500  was  required  to 
prevent  the  growth  of  others. 

Other  species  are  therefore  more  resistant  than  anthrax 
bacilli  to  the  action  of  carbolic  acid.  The  following  table  shows 
the  strength  of  various  disinfectants  required  to  hinder  or  entirely 
prevent  the  development  of  anthrax  bacilli : — 

Solution 
Iodine       .... 
Bromine  .... 
Chlorine  .... 
Osmic  acid 

Permanganate  of  potassium 
Corrosive  sublimate . 
.    AUyl  alcohol    . 
Oil  of  mustard . 
Thymol    .... 
Peppermint  oil. 
Oil  of  turpentine 
Oil  of  cloves 
Arsenite  of  potassium 
Chromic  acid    . 
Picric  acid 
Hydrocyanic  acid     . 

The  following  are  abor 

Fluid 
Boric  acid 
Borax 

Hydrochloric  acid 
Salicylic  acid    . 
Benzoic  acid     . 
Camphor  . 
Eucalyptol 
Soft  soap  . 
Quinine    . 
Hydrate  of  chloral 
Chlorate  of  potassium 
Acetic  acid 
Benzoate  of  sodium 
Alcohol     . 
Acetone    . 
Chloride  of  sodium 


Hinders 

Prevents 

1  to  5,000 

— 

1  to  1,500 

— 

1  to  1,500 

— 

1  to  1,500 

— 

1  to  3,000 

— 

1  to  1,000,000 

1  to  300,000 

1  to  167,000 

— 

1  to  330,000 

1  to  33,000 

1  to  80,000 

— 

1  to  33,000 

— 

1  to  75,000 

— 

1  to  5,000 

— 

1  to  100,000 

1  to  10,000 

1  to  10,000 

1  to  5,000 

1  to  10,000 

— 

1  to  40,000 

1  to  8,000 

the  same  strength 

as  carbolic  acid 

Hinders 

Prevents 

1  to  1,250 

1  to  800 

1  to  2,000 

1  to  700       • 

1  to  2,500 

1  to  1,700 

1  to  3,300 

1  to  1,500 

1  to  2,000 

— 

1  to  2,500 

— 

1  to  2,500 

— 

1  to  500 

1  to  5,000 

1  to  830 

1  to  625 

1  to  1,000 

— 

1  to  250 

.                 — 

1  to  250 

— 

1  to  200 

,                 — 

1  to  100 

1  to  12-5 

1  to  50  No  action  . 

— 

1  to  64 

.                *™~ 

96  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

Influence  of  the  Solvent.— Although  a  5  per  cent,  solution 
of  carbolic  acid  in  water  has  a  well-marked  destructive  action  on 
the  spores,  and  a  strong  destructive  action  on  fully-developed 
anthrax  bacilli,  a  solution  of  the  same  strength  in  oil  or  alcohol 
has  not  the  least  disinfectant  action.  A  similar  influence  with 
regard  to  iodine  is  observable  in  the  previous  tables. 

Effect  of  the  Fluid  with  which  Disinfectants  are  mixed. 
— This  is  sometimes  very  marked,  especially  in  the  case  of  free 
iodine,  bromine,  or  chlorine.  These  in  watery  solutions  are 
powerful  disinfectants,  but  when  mixed  with  fluids  which  contain 
alkalies,  e.g.  blood-serum,  they  are  converted  into  bromides, 
iodides,  and  chlorides,  and  their  action  is  very  greatly  diminished. 
The  action  of  corrosive  sublimate,  however,  and  of  ethereal  oils 
is  not  altered. 

Influence  of  Temperature  on  the  Action  of  Antiseptics.— 
The  action  of  antiseptics  is  greatly  increased  by  a  high  tempera- 
ture. Spores  of  anthrax  bacilli  exposed  to  the  vapour  of  carbolic 
acid  at  15°-20°  C.  remain  unchanged  even  after  45  days'  expo- 
sure. When  exposed  to  the  vapour  of  carbolic  acid  at  a  tem- 
perature of  55°  C.  the  case  is  very  different.  Half  an  hour's 
exposure  does  not  seem  to  harm  them  at  this  temperature,  but 
many  are  destroyed  by  an  exposure  of  an  hour  and  a  half,  and 
very  few  will  stand  3  hours'  exposure,  so  that  probably  an  exposure 
of  5  or  6  hours  would  destroy  the  whole  of  them. 

Alterations  in  Bacteria  by  Heat  and  Soil.— By  careful 
cultivation  through  successive  generations  of  a  slip  taken  from 
a  wild  fruit-tree,  the  chemical  processes  of  growth  may  be  so 
modified  in  it  that  the  fruit  will  lose  its  acrid  character  and 
become  edible  and  pleasant.  What  is  true  of  higher  plants  is 
true  also  of  lower  in  this  respect,  and  bacilli  are  much  modified 
by  the  conditions  under  which  they  are  cultivated ;  for  example, 
Pasteur  has  found  that  the  bacilli  of  anthrax  develop  and  multiply 
in  beef-tea  best  at  25V40°  C.  Their  development  is  retarded  at 
lower  or  higher  temperatures  than  these,  and  is  completely  ar- 
rested at  15°  or  43°  C.  When  cultivated  at  a  temperature  where 
development  occurs  with  difficulty,  such  as  42°-43°,  the  bacilli 
no  longer  form  resting  spores,  but  only  grow  into  long  threads. 

Fresh  bacilli  injected  into  an  animal  rapidly  cause  death 
from  anthrax,  but  the  longer  they  have  been  previously  kept  at 
this  high  temperature  the  more  does  their  virulence  decrease, 
and  at  the  end  of  four  or  six  weeks  they  die. 

When  some  of  the  first  crop  of  bacilli  are  put  into  fresh  beef- 
tea,  the  second  crop  retains  the  degree  of  virulence  of  the  first, 
and  the  third  crop  taken  from  the  second,  and  again  grown  in 
fresh  beef-tea,  has  exactly  the  same  morbific  power,  and  so  on. 

When  the  bacilli  are  cultivated  at  35°,  the  microzymes  not 
only  multiply  quickly,  but  they  form  spores  of  a  definite  degree 
of  virulence,  and  these  spores  may  be  kept  unaltered  for  years  in 


chap,  in.]    ACTION  OF  DBUGS  ON  PEOTOPLASM,  ETC.      97 

sealed  tubes,  whereas  the  threads  of  developed  bacilli  die  when 
air  is  excluded. 

When  an  animal  is  inoculated  with  anthrax  bacilli  whose 
virulence  has  been  diminished  by  cultivation  at  a  high  tempe- 
rature, they  produce  merely  temporary  illness  instead  of  death. 
By  the  growth  of  these  non-virulent  bacteria  in  the  body,  its 
constitution  appears  to  undergo  some  alteration,  and  virulent 
bacteria  subsequently  injected  have  a  much  less  powerful  action 
on  it.  If  the  first  injection  be  made  with  bacteria  having  a  very 
slight  amount  of  virulence,  the  animal  may  still  die  if  injected  a 
second  time  with  virulent  bacteria,  but  if  inoculated  first  with 
non-virulent  bacteria  and  a  second  time  with  bacteria  rather 
more  powerful,  a  slight  disturbance  is  produced  by  each  inocu- 
lation, and  a  subsequent  injection  of  virulent  bacteria  no  longer 
causes  death. 

The  changes  which  are  produced  by  inoculation  with  modified 
anthrax  or  with  vaccine  matter  in  the  blood  and  tissues,  although 
probably  very  slight,  are  sufficient  to  confer  on  the  organism 
immunity  from  further  infection.  This  is  usually  permanent, 
although  the  immunity  may  dimmish  with  the  course  of  years, 
unless  the  advancing  age  of  the  animal  in  itself  tends  to  lessen 
its  liability  to  infection. 

A  similar  immunity  against  infection  with  different  bacilli  is 
sometimes  conferred  by  age.  Thus  young  dogs  are  easily  infected 
with  anthrax,  but  old  ones  are  not. 

A  difference  of  species  also  confers  immunity.  Thus  rats 
and  field-mice  are  not  liable  to  infection  with  anthrax,  while 
house-mice  are  highly  so.  Algerian  sheep  also  resist  infection 
with  anthrax,  while  French  sheep  do  not. 

The  experiments  of  Cash  seem  to  show  that  it  may  be  possible 
by  the  action  of  drugs  to  alter  the  blood  and  tissues  in  such  a 
way  as  to  render  the  animal  proof  against  infection  by  pathogenic 
bacteria ;  for  he  has  found  that  by  the  continued  administration 
of  minute  doses  of  corrosive  sublimate  to  animals  he  can  render 
them  capable  of  resisting  the  lethal  effects  of  anthrax  subse- 
quently inoculated.1  This  is  a  direction  in  which  further  research 
is  likely  to  yield  interesting  results. 


Possible  Identity  of  Different  Forms  of  Bacteria. 

It  has  already  been  mentioned  that  we  are  not  quite  certain 
whether  all  the  species,  genera,  or  even  orders  of  bacteria  are 
natural  divisions,  or  whether  the  same  organism  under  various 
conditions  of  nutrition  and  development  may  not  present  such 
different  appearances  as  to  be  included  in  different  orders  and 

1  Cash :  Proceedings  of  the  Physiological  Society,  Dec.  12,  1885.     Journal  of 
Physiology,  vol.  vii. 


98  PHAEMACOLOGY   AND   THEEAPEUTICS.      [sect.  i. 

under  different  names.  Yet  this  is  a  matter  of  very  great  im- 
portance in  regard  to  the  causation  of  disease,  for  if  it  be  true 
that  organisms  which  are  usually  innocuous  may  undergo  an 
opposite  process  to  that  which  occurs  in  anthrax  bacilli  by  cul- 
tivation, and  may  in  certain  conditions  of  soil  be  changed  from 
innocuous  into  pathogenous  forms,  we  can  understand  how 
diseases  may  appear  to  originate  de  novo. 

It  has  been  stated  by  Naegelithat  bacteria  may  be  so  modified 
by  cultivation  as  to  form  entirely  different  fermentative  products. 
Thus  he  says  that  the  bacterium  which  produces  lactic  acid 
fermentation  in  milk  may  be  changed  by  cultivating  it  in  extract 
of  meat  and  sugar,  so  that  it  will  no  longer  produce  a  lactic  but 
an  ammoniacal  decomposition  in  milk.  He  considers  also  that 
innocuous  may  be  transformed  into  virulent  bacteria,  and  back 
again  into  an  innocuous  form,  and  Buchner  thinks  that  he  has 
succeeded  in  transforming  the  ordinary  hay -bacillus  (bacillus  sub- 
tilis)  into  anthrax  bacillus  by  cultivating  it  for  a  number  of 
generations  in  Liebig's  meat  extract,  peptone,  and  sugar.  This 
observation  is  denied  by  Klein '  and  others,  but  observations 
which  partly  support  Buchner  and  partly  Klein  have  been  made 
by  P.  Kohler,2  who  finds  that  while  the  ordinary  hay -bacillus 
(bacillus  subtilis)  is  not  altered  in  its  appearance  by  repeated 
cultivations,  it  acquires  a  progressive  virulence  which  renders  it 
so  fatal  to  animals  as  to  resemble  the  anthrax  bacillus  in  its 
deadly  properties. 

H.  C.  Wood  and  Formad 3  have  also  come  to  the  conclusion 
that  the  micrococci  found  in  diphtheria  resemble  those  on  furred 
tongues  in  all  respects  excepting  in  their  greater  tendency  to  grow. 
When  cultivated  successively,  they  lose  their  contagious  power 
and  grow  less  readily.  These  authors,  therefore,  consider  that 
circumstances  outside'  the  body  are  capable  of  converting  the 
slower  growing  or  common  micrococcus  into  the  rapidly  growing 
micrococcus  of  diphtheria,  which,  when  cultivated  again,  reverts 
to  the  common  type. 

Action  of  Bacteria  and  their  Products  on  the  Animal 
Body. — When  bacteria  are  injected  into  the  animal  body,  they 
produce  different  effects  according  to  the  original  nature  of  the 
bacteria  or  bacilli,  the  conditions  under  which  they  have  been 
cultivated,  and  the  quantity  introduced.  There  is  probably 
another  factor  of  no  less  importance,  which,  however,  still  re- 
quires to  be  investigated,  viz.  the  condition  of  the  body  (p.  97) 
into  which  they  are  introduced.  In  considering  the  effect  of  an 
injection  into  the  living  body  of  a  solution  containing  bacilli,  we 
must  be  careful  to  distinguish  between  the  effect  of  the  bacilli 
themselves,  after  their  introduction  into  the  circulation,  upon  the 

'  Klein,  Quarterly  Journ.  of  Microscopic  Science,  Jan.  1883. 

2  Inaugural  Dissertation  (Gottingen),  1881. 

*  National  Board  of  Health  Bulletin,  Siipplement  No.  17,  Jan.  21,  18f>2. 


chap.  iii.J    ACTION  OP  DEUGS  ON  PEOTOPLASM,  ETC.      99 

tissues  and  organs  of  the  body,  and  the  effect  of  the  substances 
which  they  have  already  formed  in  the  solution  before  their 
injection. 

We  must  distinguish  between  those  two  things  in  the  same 
way  as  we  would  have  to  distinguish  between  the  effects  of  the 
particles  of  the  yeast-plant  and  the  effects  of  the  alcohol  which 
it  had  formed,  if  we  were  to  inject  a  solution  in  which  yeast  was 
growing  into  the  veins  of  an  animal.  The  yeast  or  the  bacteria 
would  have  one  effect  upon  the  animal,  the  alcohol  or  the  septic 
products  of  the  bacteria  would  have  another. 

Solutions  of  putrid  organic  matter  containing  numerous 
bacteria  cause  high  fever  and  often  death. 

The  course  of  the  fever  depends  on  the  specific  nature  of  the 
bacteria,  e.g.  septic  bacteria,  anthrax  bacilli,  &c. 

It  is  difficult  at  present  to  ascertain  exactly  how  far  all  the 
following  diseases  are  due  to  the  presence  of  microbes  or  their 
products  ;  but  it  has  been  found  that  micrococci  cause  erysipelas, 
acute  necrosis,  gonorrhoea,  gonorrhceal  ophthalmia,  contagious 
ophthalmia,  ophthalmia  neonatorum,  and  are  present  in  pyaemia, 
puerperal  fever,  ulcerative  endocarditis,  infective  myositis,  and 
contagious  pneumonia.  When  malignant  oedema  or  traumatic 
gangrene  occur,  bacilli  are  usually  found.  Micrococci  are  also 
supposed  by  some  to  be  the  cause  of  vaccinia  and  of  diphtheritic 
inflammation.  The  bacillus  anthracis  produces  anthrax  ;  bacillus 
septicaemiae,  blood-poisoning ;  bacillus  malariae,  ague  and  mala- 
rious diseases ;  bacillus  tuberculosis,  phthisis ;  bacillus  leprae, 
leprosy ;  and  another  bacillus  is  the  cause  of  glanders.  In  re- 
lapsing fever  the  spirochaeta  Obermeyeri  is  found  in  the  blood, 
and  is  probably  the  cause  of  the  disease. 

Alkaloids  formed  by  Putrefaction.  Ptomaines. — From 
decomposing  organic  matter  substances  can  be  separated  which 
have  all  the  characters  of  alkaloids. 

The  alkaloids  produced  by  putrefaction  are  usually  known 
by  the  name  of  ptomaines.  It  was  at  one  time  supposed  that 
they  were  different  in  their  chemical  nature  from  the  alkaloids 
which  occur  in  plants,  and  they  were  supposed  to  have  a  much 
greater  reducing  power  than  the  latter.  It  was  therefore  pro- 
posed to  distinguish  between  ptomaines  and  other  alkaloids  by 
the  addition  of  potassium  ferricyanide :  if  the  alkaloid  changed 
this  into  ferrocyanide,  so  that  a  precipitate  of  prussian  blue  was 
obtained  on  the  addition  of  ferric  chloride,  it  was  supposed  to 
belong  to  the  class  of  ptomaines ;  whereas  non-reduction  was 
supposed  to  show  that  it  belonged  to  the  vegetable  alkaloids. 
It  was  soon  found,  however,  that  this  test  was  not  trustworthy, 
for  such  important  alkaloids  as  morphine  and  veratrine  produced 
reduction.  Later  researches,  especially  those  of  Brieger,  have 
shown  that  some  at  least  of  the  so-called  ptomaines  are  identical 
with  vegetable  alkaloids. 

H  2 


100  PHAEMAC0LOGY  AND   TSBEAPEUTICS.     [sect.  i. 

We  may  indeed  now  regard  alkaloids  as  products  of  albu- 
minous decomposition,  whether  'their  albuminous  precursor  be 
contained  in  the  cells  of  plants  and  altered  during  the  pro- 
cess of  growth,  or  whether  the  albuminous  substances  undergo 
decomposition  from  the  presence  of  microbes,  either  outside  or 
inside  the  animal  body,  or  by  the  pimple  process  of  digestion  by 
unorganised  ferments  such  as  pepsine. 

The  alkaloidal  products  formed  by  the  putrefaction  of  albu- 
minous substances,  vary  according  to  the  stage  of  decay  at  which 
they  are  produced.  At  first  the  poisonous  action  of  these  pro- 
ducts may  be  slight.  As  decomposition  advances,  the  poisons 
become  more  virulent ;  but  after  a  longer  period  they  appear  to 
become  broken  up  and  lose  to  a  great  extent  their  poisonous 
power. 

Muscarine,  which  is  the  poisonous  alkaloid  of  some  mush- 
rooms, has  been  made  synthetically  by  Schmiedeberg  and  Har- 
nack  from  choline ;  and  Brieger  has  obtained  from  decomposing 
albuminous  substances  several  well-defined  chemical  bodies— 
dimethylamine,  trimethylamine,  triethylamine,  ethylenediamine, 
choline,  neurine,  neuridine,  muscarine,  gadinine,  cadaverine, 
putrescine,  saprine,  and  mydaleine,  as  well  as  some  substances  to 
which  he  has  given  no  name.  Muscarine,  neurine,  and  choline 
all  have  a  similar  action,  their  power  diminishing  in  the  order 
just  mentioned,  choline  being  much  weaker  than  the  other  two. 
They  all  produce  salivation,  diarrhoea,  vomiting,  dyspnoea,  para- 
lysis, and  death.  Muscarine  and  neurine  in  frogs  produce  com- 
plete stoppage  of  the  heart  in  diastole  ;  in  mammals  they  only 
weaken  its  action.  Neurine,  cadaverine,  putrescine,  and  saprine 
have  no  marked  physiological  action ;  but  one  alkaloid  which 
Brieger  has  isolated  from  human  cadavers  in  an  advanced  stage 
of  decomposition  appears  to  affect  the  intestine,  causing  enormous 
peristalsis,  continuous  diarrhoea,  lasting  for  days,  and  extreme 
weakness.  Mydaleine,  obtained  from  a  similar  source,  is  interest- 
ing, inasmuch  as  it  causes  a  rise  of  temperature  ;  for  frequently 
we  find  in  cases  of  acute  disease  that  the  rise  of  temperature 
coincides  with  the  constipation,  and  is  removed  by  purgation,  so 
that  the  question  arises  how  far  the  rise  of  temperature  in  such 
cases  may  be  due  to  the  absorption  of  poison  from  the  intestine. 
Mydaleine  causes  dilatation  of  the  pupil,  enormous  secretion  of 
tears,  saliva,  and  sweat,  vomiting,  diarrhoea,  paralysis,  convulsions, 
twitching,  dyspnoea,  coma,  and  death. 

Sepsine,  which  was  isolated  by  Bergmann  and  Schmiedeberg 
from  putrefying  yeast,  causes  vomiting,  diarrhoea,  and  bloody 
stools ;  but  Nicati  and  Kietsch '  have  produced  choleraic  symptoms 
in  animals  by  cultivations  of  Koch's  comma  bacillus  from  which 
the  organisms  themselves  had  been  removed;  and  somewhat 

5 

1  Compt.  rend.,  xo.  928. 


chap,  in.]    ACTION  OF  DEUGS  ON  PROTOPLASM,  ETC.    101 

similar  results  were  obtained  several  years  ago  by  Lewis  and 
Douglas  Cunningham  with  cholera  stools  in  which  any  organisms 
present  had  been  destroyed  by  boiling. 

The  extract  from  putrefied  maize  has  a  tetanic  and  narcotic 

,  action,  which  appears  to  be  due  to  two  different  substances. 

These  are  not  present  in  the  same  proportion,  so  that  sometimes 

the  tetanising  action,  and  at  other  times  the  narcotic  action,  is 

most  marked. 

Another  alkaloid,  resembling  atropine  in  its  action,  has  been 
separated  by  Sonnenschein  and  Zuelzer  from  decomposing  animal 
matter ;  and  this  has  also  been  found  in  the  bodies  of  persons 
dying  from  typhus  fever. 

Another  which  resembles  curare  in  its  action  has  been  separated 
by  Guareschi  and  Mosso '  from  putrefying  brain. 

Another  substance  causing  tetanic  symptoms  has  also  been 
obtained  from  animal  matter. 

Leucomaines. — Gautier,  to  whom  much  of  our  knowledge 
regarding  alkaloids  produced  by  albuminous  decomposition  is 
due,  has  given  the  name  of  leucomaines  to  alkaloids  which  are 
not  produced  by  putrefaction  due  to  bacteria,  but  are  formed  by 
the  decomposition  of  albuminous  matters  in  the  normal  processes 
of  waste  in  the  living  animal  tissues.  Amongst  these  he  reckons 
various  substances  formed  in  muscles  and  allied  to  xanthine  and 
creatine.2 

Brieger  has  shown  that  during  the  digestion  of  fibrin  by 
pepsin  an  alkaloid  has  been  formed,  to  which  he  gives  the  name 
of  peptotoxin. 

Absorption  and  Elimination  of  Ptomaines  and  Leuco- 
maines.— It  is  probable  that  a  considerable  production  of  alkaloids 
takes  place  in  the  intestine,  both  when  the  digestive  processes 
are  normal  and  more  especially  when  they  are  disordered ;  at  the 
same  time  alkaloids  are  being  formed  in  the  muscles,  and  pos- 
sibly also  in  other  tissues.  Were  all  the  alkaloids  to  be  retained 
in  the  body,  poisoning  would  undoubtedly  ensue,  and  Bouchard 
considers  that  the  alkaloids  formed  in  the  intestine  of  a  healthy 
man  in  twenty-four  hours  would  be  sufficient  to  kill  him  if  they 
were  all  absorbed  and  excretion  stopped.  He  finds  that  the 
poisonous  activity  of  even  healthy  human  faeces  is  very  great, 
and  a  substance  obtained  from  them  by  dialysis  produced  violent 
convulsions  in  rabbits.  When  the  funcdons  of  the  kidney  are  im- 
paired, so  that  excretion  is  stopped,  uraemia  occurs,  and  Bouchard 
would  give  the  name  of  stercoraemia  to  this  condition,  because  he 
believes  it  to  be  due  to  alkaloids  absorbed  from  the  intestines 
He  also  thinks  that  the  nervous  disturbance  which  occurs  in 
cases  of  dyspepsia  is  due  to  poisoning  by  ptomaines.     That 

1  Les  Ptomaines,  Turin,  1883. 
Sur  les  alcalcfides  dirivis  de  la  ctestruoticn  hacU.-ienne  ou  physiologig^ue  des 

animaux.    Paris :  G.  Masson.     1886. 


102  PHARMACOLOGY   AND   THERAPEUTICS,      [sect.  i. 

alkaloids  are  excreted  by  the  urine  has  been  shown  by  Bocci, 
■who  has  found  in  the  urine  a  substance  having  an  action  like 
that  of  curare. 

Effect  of  Drugs  on  the  Action  of  Bacteria  in  the  Animal 

Body. 

So  long  as  bacteria  are  outside  the  body,  we  may  use  drugs 
of  any  strength  we  please  to  destroy  them,  but  the  case  is  quite 
different  when  they  have  once  gained  entrance  and  are  no  longer 
outside  but  inside  the  body,  because  then  the  nature  of  the  drug 
and  the  amount  we  can  employ  is  limited  by  its  effect  on  the 
organism  itself,  and  we  cannot  administer  very  large  doses  of 
antiseptics  leBt  we  should  injure  or  kill  the  patient  at  the  same 
time  that  we  destroy  the  bacteria  which  are  causing  the  disease. 
All  that  we  can  hope  to  do  is  to  turn  the  scale,  if  possible,  in 
favour  of  the  organism  in  the  struggle  for  existence  between  the 
cells  which  compose  it  and  the  bacteria  which  have  invaded  it 
(vide  pp.  86  and  89). 

Our  hope  of  doing  this  rests  on  the  fact  that  drugs  which 
may  be  injurious  both  to  the  tissue  and  to  the  bacteria  are  not 
equally  so  to  each.  Thus  excess  of  temperature  is  injurious  to  the 
organism,  but  it  is  also  destructive  to  bacteria ;  and,  as  Fokker ' 
has  pointed  out,  the  febrile  reaction  which  occurs  on  the  intro- 
duction of  bacteria  into  the  blood  may  be  a  means  of  destroying 
the  mierobes  and  preserving  the  animal.  There  is  often  a  germ 
of  truth  in  apparently  foolish  plans  of  treatment,  and  the  old 
practice  of  treating  scarlet  fever,  small-pox,  and  measles  by  warm 
drinks,  hot  rooms,  and  abundant  clothing  may  have  been  a  blind 
effort  to  aid  the  natural  processes  of  cure,  just  as  the  irritating 
ointment  of  the  Middle  Ages  seems  to  have  been  an  attempt  at 
antiseptic  surgery.  The  extraordinary  destructive  power  of  cor- 
rosive sublimate,  and  the  fact  that  it  continues  to  act  in  blood- 
serum  just  as  it  does  in  distilled  water,  seem  to  indicate  that 
it  might  be  used  to  destroy  bacilli  in  the  body,  especially  as 
Schlesinger  has  found  that  it  may  be  injected  subcutaneously 
into  rabbits  and  dogs  daily  for  several  months  without  doing 
them  any  harm,  even  in  doses  of  5  milligrammes,  1  cc.  of  a  \  per 
cent,  solution.  Koch's  experiments  on  this  point,  by  the  adminis- 
tration of  sublimate  after  inoculation  with  anthrax,  led  to  a 
negative  result,  the  animals  inoculated  with  anthrax  dying  of  the 
disease,  notwithstanding  the  injection  of  the  sublimate.  On  the 
other  hand,  Cash  has  succeeded  in  preventing  death  from  anthrax 
by  administering  corrosive  sublimate  for  some  time  previous  to 
inoculation  (p.  97). 

The  extraordinary  effect  of  allyl  alcohol,  and  the  less  power- 

1  International  Medical  Congress,  1881. 


chap,  in.]    ACTION  OF  DEUGS  ON  PEOTOPLASM,  ETC.     103 

ful  but  still  great  action  of  ethereal  oils,  indicate,  however,  that 
we  may  look  forward  with  hope  to  the  discovery  of  some  organic 
substances  which  may  so  hinder  the  development  of  bacteria  in 
the  body  after  their  inoculation,  as  to  allow  of  their  gradual  de- 
struction in  the  organism,  and  prevent  the  sickness  or  death 
which  they  would  otherwise  have  occasioned. 

In  relation  to  this,  the  observations  of  the  late  Dr.  W.  Farr 
in  his  Keport  are  very  interesting :  '  Alcohol  appears  to  arrest 
the  action  of  zymotic  diseases,  as  it  prevents  weak  wines  from 
fermenting ;  like  camphor,  alcohol  preserves  animal  matter — this 
is  not  now  disputed.  But  may  it  not  do  more?  May  it  not 
prevent  the  infection  of  some  kinds  of  zymotic  disease  ? ' 

Experiments  have  shown  that  alcohol  itself  has  but  a  slight 
power  in  destroying  bacilli,  but  it  is  possible  that  even  the  slight 
traces  of  the  ethers  which  are  present  in  wine  or  spirits  may 
have  some  beneficial  action  in  cases  of  septic  poisoning. 

Antiseptics,  Antizymotics,  Disinfectants,  Deodorizers. 

These  classes  of  remedies  are  often  confounded  together.  It 
is  well,  however,  to  distinguish  their  meanings : — 

Antizymotics  are  remedies  which  arrest  fermentation. 

It  has  already  been  mentioned  (p.  73etseq.)  that  fermentative 
processes  may  depend  upon  either  enzymes  or  organised  ferments, 
and  that  organised  ferments  maybe  subdivided  into  several  classes, 
such  as  those  consisting  of  yeast,  innocuous  bacteria,  and  patho- 
genic bacteria. 

The  class  of  antizymotics  includes  all  substances  which  arrest 
fermentative  processes  due  to  these  bodies.  It  contains  two  sub- 
classes :  antiseptics  and  disinfectants. 

Antiseptics  are  remedies  which  arrest  putrefaction.  They 
do  this  by  preventing  the  development,  or  completely  destroying 
the  bacilli  on  which  septic  decomposition  depends. 

Disinfectants  are  remedies  which  destroy  the  specific  poisons 
of  communicable  diseases.  Many  of  those  poisons,  perhaps  all 
of  them,  belong  to  the  class  of  microbes,  and  so  disinfectants 
may  be  regarded  as  a  sub-class  of  antizymotics. 

Deodorizers  or  deodorants  are  remedies  which  destroy  dis- 
agreeable smells.  Such  smells  often  accompany  the  decomposi- 
tion of  various  organic  substances,  which  septic  organisms  cause. 
These  foul-smelling  products  may  be  injurious  to  health  in  them- 
selves by  acting  as  poisons ;  but  they  are  not  to  be  confounded 
with  the  bacteria  which  produce  them.  Moreover,  the  disagree- 
able nature  of  the  smell  is  not  always  to  be  relied  upon  as  an 
index  of  its  poisonous  nature.  M.  Gustav  le  Bon  made  some 
experiments  with  hashed  meat  and  water,  over  which  he  put 
some  small  animals.  As  the  meat  decomposed,  the  liquid  teemed 
with  organisms,  was  very  fatal  when  injected  into  an  animal, 


104  PHAEMACOLOGY  AND   THEBAPEUTICS.      [sect.  I. 

and  emitted  a  very  foul  smell,  which,  however,  did  not  seem  to 
be  very  injurious.  Afterwards  the  organisms  present  in  the 
liquid  died,  and  the  foul  smell  became  much  less  disagreeable ; 
but  the  emanations  from  the  liquid  appeared  to  become  much 
more  poisonous,  although  the  liquid  itself,  when  injected  into  an 
animal,  had  no  longer  the  same  virulent  power  as  at  first. 

Uses  of  Antiseptics. — Antiseptics  are  employed  externally 
in  order  to  destroy  microbes  before  their  entrance  into  the  body, 
and  are  administered  internally  with  a  like  object,  or  for  the 
purpose  of  at  least  preventing  the  free  development  and  multi- 
plication of  the  microbes. 

They  are  employed  externally  in  surgical  operations,  with 
the  object  of  destroying  any  organisms  which  might  find  a  nidus 
in  the  wound,  and  there  give  rise  to  the  formation  of  poisonous 
substances.  Both  these  substances  and  the  bacteria  themselves 
will  not  only  have  an  injurious  local  action  in  the  wound,  but  by 
undergoing  absorption  may  prove  injurious  or  fatal  to  the  or- 
ganism as  a  whole.  The  antiseptic  plan  of  treatment  has  been 
empirically  practised  in  a  limited  manner  for  a  very  long  period 
without  its  principle  being  recognised :  for  the  well-known  Friar's 
balsam  has  antiseptic  properties.  It  is  to  Lister  that  we  owe 
the  introduction  of  such  a  mode  of  treatment,  not  based  upon 
mere  empiricism,  but  upon  scientific  knowledge.  The  reason 
why  it  had  fallen  into  disuse  probably  was  that  some  of  the  anti- 
septic substances  used  for  dressing  wounds  in  the  Middle  Ages 
were  irritants  as  well  as  antiseptics.  Those  who  employed  them 
did  not  know  the  reason  why  they  were  beneficial,  and  supposed 
that  their  virtue  was  due  to  their  irritating  properties.  The  oint- 
ments were  accordingly  made  more  and  more  irritating :  and 
thus  more  harm  than  good  was  done,  until  they  were  discarded 
by  Ambrose  Pare.  The  antiseptic  most  commonly  employed  is 
carbolic  acid.  Not  only  are  all  the  instruments  to  be  employed 
disinfected  by  a  watery  solution,  but  the  operation  itself  is  con- 
ducted under  a  spray  of  the  dilute  acid,  so  as  to  render  innocuous 
any  organisms  which  may  be  present  in  the  air.  The  wound 
is  then  covered  with  an  antiseptic  dressing.  Whenever  this 
requires  to  be  removed  it  must  always  be  done  under  the  spray. 
The  reason  of  these  great  precautions  is  obvious  :  if  any  germs, 
however  few,  gain  an  entrance  they  will  soon  multiply  and  prove 
as  deadly  as  a  great  number,  the  only  difference  being  one  of  time. 

The  great  danger  which  may  arise  from  an  exceedingly 
minute  portion  of  septic  matter  renders  great  caution  necessary 
on  the  part  of  those  who  might,  by  a  little  indiscretion,  convey  it 
from  one  to  another.  Thus  a  number  of  years  ago  a  medical 
man  was  nearly  driven  mad  by  an  epidemic  of  puerperal  fever 
which  he  had  in  his  practice :  one  patient  dying  after  the  other. 
In  order  to  get  rid  of  any  infection,  he  burnt  all  his  clothes  and 
went  away  for  three  months.     During  his  absence  everything 


chap,  in.]    ACTION  OP  DEUGS  ON  PEOTOPLASM,  ETC.    105 

went  well.  On  his  return  the  epidemic  again  broke  out :  on 
careful  investigation  he  found  the  only  thing  he  had  forgotten  to 
burn  was  his  gloves,  and  these  had  acted  as  a  reservoir  of  in- 
fection. The  hands,  imperfectly  cleansed  in  the  first  instance, 
had  coiiveyed  the  septic  matter  into  the  gloves,  and  there  it  re- 
mained, re- infecting  the  hands  every  time  the  gloves  were  put  on. 
In  the  same  way  a  thermometer  may  prove  a  cause  of  continual 
infection  unless  the  thermometer  be  carefully  washed,  and,  if 
necessary,  disinfected,  each  time  it  is  used  and  before  it  is  put 
into  the  case.  In  a  similar  manner  it  has  been  found  tna,t 
gonorrhceal  matter  may  remain  in  the  vagina  and  infect  several 
persons  without  the  woman  herself  ever  suffering.  One  of  the 
best  antiseptics  for  disinfection  in  such  cases  is  permanganate  of 
potassium.  This  may  be  used  to  wash  out  abscesses,  if  there 
is  any  fear  of  danger  from  absorption  of  carbolic  acid  ;  and  also 
as  a  lotion  for  ulcers  or  wounds  about  the  mouth,  the  urethra, 
or  anus,  where  the  carbolic  acid  might  be  too  irritating ;  as  is 
evident  from  Koch's  experiment,  however  (vide  p.  92),  a  solution 
of  the  strength  ordinarily  used — one  per  cent.,  i.e.  four  grains  to 
the  ounce — is  not  sufficient  to  destroy  the  septic  organism, 
although  one  of  five  times  the  strength  will  do  so. 

Another  way  in  which  septic  poisoning  may  be  produced  is 
,by  the  introduction  of  a  catheter  into  the  bladder,  where  this 
cannot  be  completely  emptied  naturally  on  account  either  of 
paralysis,  enlarged  prostate,  or  stricture.  So  long  as  the  con- 
tents of  the  bladder  have  not  come  in  contact  with  any  foreign 
matter  they  may  remain  in  the  bladder  for  some  time  without 
undergoing  decomposition,  but  if  a  dirty  catheter  should  be 
passed,  and  thus  a  few  organisms  introduced  into  the  bladder, 
decomposition  may  set  up  in  the  urine  and  septic  poisoning 
ensue.  A  solution  of  carbolic  acid  in  oil  is  sometimes  trusted 
to  for  the  disinfection  of  catheters,  but,  as  Koch's  experiments 
(p.  96)  show  that  such  a  solution  has  little  or  no  antiseptie 
power,  the  catheters  should  be  disinfected  by  a  strong  solution 
of  carbolic  acid  in  water,  and  afterwards  oiled  before  their 
introduction. 

The  use  of  antiseptics  internally  is  limited  by  the  resistance 
of  the  organism  itself,  as  already  mentioned  (p.  102).  In  the 
stomach  antiseptics  are  used  for  the  purpose  of  preventing  decom- 
position, and  by  thus  lessening  the  production  of  irritating  pro- 
ducts they  diminish  irritation  of  the  stomach  and  arrest  vomiting. 
Tbose  which  are  chiefly  employed  for  this  purpose  are  creasote, 
carbolic  acid,  sulpho-carbolates,  salicylic  and  sulphurous  acids. 
In  the  intestine  antiseptics  are  useful  in  arresting  putrefaction, 
and  thus  preventing  the  harm  caused  locally  to  the  intestine 
by  the  products  of  decomposition  as  well  as  the  injury  due  to 
their  subsequent  reabsorption.  They  therefore  tend  to  check 
diarrhcea  and  dysentery.    It  is  probably  to  its  antiseptic  action 


106  PHAEMACOLOGY  AND   THEKAPEUTICS.      [sect.  i. 

that  currosive  sublimate  owes  its  curative  power  in  cases  of  in- 
fantile dysentery,  and  it  is  not  improbable  that  the  beneficial 
action  of  calomel  is  due  to  a  similar  action,  for  it  has  been  found 
by  Wassilieff  greatly  to  retard  the  decomposition  due  to  low 
organisms . 

The  beneficial  action  of  mercurials  in  such  cases  may  be 
partly  due  to  their  antiseptic  power  not  being  as  greatly  diminished 
by  admixture  with  fecal  matters  as  that  of  other  antiseptics. 
After  absorption  into  the  blood,  antiseptics  are  chiefly  employed  in 
febrile  conditions,  in  order,  if  possible,  both  to  lessen  the  growth 
o'f  the  septic  organism  and  to  remove  the  danger  to  the  individual 
which  the  fever  itself  would  occasion.  The  principal  antiseptics 
used  for  this  purpose  are  alcohol,  eucalyptol,  quinine,  salicin, 
salicylic  acid,  and  salicylates.  Carbolic  acid  and  creasote  can 
hardly  be  used,  as  their  action  on  the  organism  is  too  poisonous, 
but  hydroquinone,  cresotinic  acid,  kairin,  pyrocatechin,  anti- 
pyrin,  and  resorcin  are  not  markedly  poisonous,  and  are  antir 
pyretic.  They  may  thus  be  useful,  and  antipyrin  is  now  largely 
employed  (vide  also  Antipyretics).  Eucalyptol  has  sometimes 
appeared  to  me  to  be  more  beneficial  in  cases  of  septic  poisoning 
ihan  quinine  ;  at  any  rate,  I  have  seen  patients  recover  under  its 
use  who  had  not  been  benefited  by  quinine. 

Disinfectants. — These  are  generally  employed  in  order  to 
destroy  the  germs  of  disease  in  the  excreta  of  a  patient  suffering 
from  an  infectious  disease,  or  those  germs  which  may  be  adhering 
to  articles  of  clothing  or  to  furniture  or  to  the  walls  of  a  room  in 
which  the  patient  has  been  lying.  Probably  the  most  efficient 
and  generally  applicable  to  articles  of  clothing  is  heat.  The  heat 
employed  is  usually  from  230°  to  250°  P.,  but  as  a  general  rule 
it  should  be  as  hot  as  the  fabrics  will  bear  without  injury,  and 
should  be  continued  as  long  as  is  necessary  to  raise  the  central 
parts  of  the  articles  to  be  disinfected  to  the  temperature  of  the 
chamber  in  which  they  are  placed.  As  the  presence  of  moisture  aids 
the  destructive  action  of  heat  upon  septic  organisms,  superheated 
steam  appears  to  be  the  best  disinfectant  under  ordinary  circum- 
stances. The  only  disinfectant  that  seems  to  be  really  trust- 
worthy for  destroying  septic  organisms  when  it  is  simply  washed 
over  them  is  corrosive  sublimate  :  even  in  a  dilution  of  one  to  a 
thousand  it  appears  to  destroy  microzymes  and  their  spores  by  a 
single  application  for  a  few  minutes. 

Deodorizers. — Deodorizers  are  mainly  strong  oxidizing  and 
deoxidizing  substances,  as  chlorine  and  its  oxides,  sulphurous 
acid,  nitrous  acid,  ozone,  peroxide  of  hydrogen,  permanganate  of 
potassium.  Charcoal,  in  addition  to  oxidizing,  absorbs  and  con- 
denses the  foul-smelling  gas.  Those  which  are  most  commonly 
used  as  deodorizers  for  the  air  of  rooms  are  chlorine  or  its  oxides 
set  free  from  chlorinated  lime. 

For  removing  smells  from  the  hands,  carbolic  acid  is  to  be 


chap,  in.]    ACTION  OF  DEUG8  ON  PROTOPLASM,  ETC.    107 

preferred  to  others,  and  for  deodorizing  faecal  matters,  perman- 
ganate of  potassium,  carbolic  acid,  or  charcoal.  A  mixture  of 
eight  or  nine  parts  calcined  dolomite  (magnesia  and  lime)  with 
one  or  two  of  peat  or  wood  charcoal  is  not  only  an  excellent 
deodorizer,  but  increases  the  value  of  the  faecal  matters  as  manure. 


Antiperiodics. 

These  are  remedies  which  lessen  the  severity  or  prevent 
the  return  of  attacks  of  certain  diseases  which  tend  to  recur 
periodically. 

The  chief  of  these  are : — 

Cinchona  bark  and  its  alkaloids : — 

Quinine.  Arsenic. 

Cinchonine.  Salicylic  acid. 

Quinidine.  Salicylates. 

Cinchonidine.  Salicin. 

Bebeeru  bark  and  its  alkaloid  : — 

Bebeerine.  Eucalyptol. 

Action. — The  mode  in  which  antiperiodics  act  is  not  at 
present  definitely  ascertained,  nor  indeed  is  the  pathology  of 
the  diseases  which  they  prevent.  Bemittent  fever,  however,  has 
been  shown  to  depend  upon  the  presence  of  a  spirillum  in  the 
blood,  and  there  is  considerable  evidence  for  considering  that 
malarious  conditions  are  connected  with  the  presence  of  a  bacillus. 
The  periodical  return  of  the  attacks  in  such  diseases  would  ap- 
pear, then,  to  be  associated  with  the  growth  of  successive  crops 
of  these  protophytes,  and  the  action  of  antiperiodics  might  be 
explained  by  supposing  that  they  interfere  with  the  development 
of  these  pathogenic  organisms. 

Uses. — Quinine  and  cinchona  bark  are  often  regarded  as 
almost  specific  in  the  various  affections  due  to  malarious  poison- 
ing, i.e.  intermittent  fevers,  periodic  headaches,  neuralgias,  etc. 
In  tropical  remittent  fever  of  malarious  origin,  quinine  is  also 
the  best  remedy  we  possess.  It  must  be  given  in  very  large  doses, 
however,  and  is  less  certainly  curative  than  in  intermittent  fever. 
The  other  cinchona  alkaloids  have  a  similar  action  to  quinine^ 
but  are  not  quite  so  powerful :  they,  as  also  quinine,  may  be  used 
as  prophylactics  in  order  to  prevent  the  recurrence  of  ague  in 
persons  travelling  through  or  living  in  malarious  districts  as 
well  as  for  the  purpose  of  curing  malarious  conditions  already 
present. 

Arsenic  is  sometimes  even  more  powerful  than  quinine,  but  as 
a  rule  it  answers  best  in  malarious  conditions  which  are  some- 


108  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

times  known  as  masked  or  latent  malaria,  and  which  manifest 
themselves  in  neuralgia  and  nervous  or  digestive  disturbance 
rather  than  in  well-marked  ague  fits. 

Adjuncts. — Emetics  and  purgatives  aid  the  action  of  anti- 
periodics,  and  sometimes,  indeed,  can  replace  them  and  cure  ague 
without  their  aid.  Antiperiodics  rarely  succeed  if  the  functions 
of  the  liver  are  disturbed  unless  they  are  aided  by  emetics  or 
purgatives,  and  especially  by  cholagogues. 


109 


CHAPTEE  IV. 
ACTION  OF  DEUGS  ON  INVEETEBEATA. 

The  study  of  the  action  of  drugs  on  invertebrata  has  not  been 
carried  out  methodically  to  any  great  extent,  but  it  offers  a  very 
promising  field  for  investigation,  and  probably  in  the  course  of  a 
few  years  may  yield  very  valuable  results. 

Action  of  Drugs  upon  Medusa. 

This  subject  has  been  worked  at,  almost  exclusively  by  Eomanes '  and 
Krukenberg.8  At  present  it  has  little  practical  bearing,  but  it  promises  to  be 
of  great  service  by  enabling  us  to  understand  better  the  action  of  drugs  on 
contractile  structures  generally,  and  on  the  heart  in  particular. 

In  medusae  the  swimming  organ  consists  of  a  bell-shaped  mass  of  con- 
tractile substance,  within  which  the  polyp  hangs  like  the  clapper.  Around 
the  margin  of  this  bell  are  a  number  of  ganglia  connected  with  one  another 
by  nervous  filaments,  and  forming  a  peripheral  ring. 


Lithocvst  and  ganglion  M         ;;  HPolypite. 

Tentacles   9|    9IUII 


Flo.  29.— Medusa  (Sarsia),  natural  size. 


In  the  normal  state  of  the  animal,  the  bell  alternately  contracts  and  dilates 
rhythmically,  so  that  the  animal  is  propelled  through  the  water. 

When  the  marginal  strip  containing  the  ganglia  is  removed,  the  bell 
becomes  entirely  motionless.  The  bell  thus  resembles,  as  we  shall  see  after- 
wards, the  ventricle  of  the  frog's  heart,  both  in  the  relation  of  ganglia  to  it, 
and  in  its  rhythmical  movements.  Oxygen  accelerates,  and  carbonic  acid 
slows  and  finally  stops,  the  rhythmical  movements. 

When  the  bell,  paralysed  by  the  removal  of  the  ganglia  which  supply  its 
normal  stimulus  to  motion,  is  momentarily  stimulated  by  a  single  induction 
shock,  it  invariably  responds  by  a  single  contraction. 

1  Eomanes,  Phil.  Trans,  vol.  clxvi.  part  1,  and  vol.  clxvii.  part  2, 1866  and  1867. 
!  Krukenberg,  Vergleichend.  physiologische  Studien,  Heidelberg,  1880. 


110  PHAEMACOLOGY  AND   THEKAPEUTICS.      [sect.  i. 

When  successive  shocks  are  employed  at  regular  intervals  the  effect  of 
each  increases  until  the  maximum  is  reached  (Fig.  30,  cf.  pp.  122  and  123). 


Fig.  30. — Shows  the  increasing  contractions  of  the  tissue  of  the  medusa  whien  stimulated  by  repeated 
weak  induction  shocks  of  the  same  intensity.  The  first  two  shocks  had  no  apparent  effect,  and 
the  first  feeb'e  contraction  seen  in  the  figure  was  caused  by  the  third  shock.  (From  a  paper  by 
Bomanes  in  Phil,  Trans.) 

But  if  an  additional  constant  stimulus  is  supplied  to  it  by  the  addi- 
tion of  acid  to  the  water  in  which  it  is  floating ;  by  the  passage  of  a  constant 
or  of  an  interrupted  electrical  current  through  it ;  or  by  alcohol  or  glycerine 
dropped  upon  its  surface,  it  commences  to  beat  regularly,  rhythmically,  and 
continuously.  When  rhythmical  action  is  thus  artificially  induced  in  the 
paralysed  bell,  its  rate  is  increased  by  raising  the  temperature,  and  re- 
duced by  cooling  it.     Temperatures  below  20°  or  above  85°  arrest  the  rhythm. 

When  the  marginal  strip  containing  the  ganglia  is  cut  off  and  left  attached 
only  at  one  point,  a  stimulus  applied  to  its  end  travels  along  the  strip  and 
finally  causes  the  bell  to  contract.     The  stimuli  which  pass  along  may  be 


Strip  of  contractile  tissue  witS  ■  WHmm/M9    ' 

fringe  of  tentacles H  t' 

Fro.  31.— Diagram  of  a  medusa  (tiaropsis),  about  one-third  natural  size,  with  a  strip  of  contractile 
tissue  cut  from  the  bell,  but  left  attached  at  one  end. 

of  two  kinds — they  may  occur  separately  or  together.  The  first  kind  is  a 
wave  of  contraction  in  the  contractile  tissue  of  the  strip  itself.  If  the  stimulus 
is  applied  to  a  portion  of  the  strip  the  contraction  will  pass  along  like  a  wave 
until  it  reaches  the  bell,  which  it  excites  to  contraction.  The  second  is  a 
rudimentary  form  of  nervous  activity.  This  may  occur  along  with  the  con- 
traction wave,  and  when  this  is  the  case  it  is  seen  to  pass  along  in  front  of 
the  contractile  wave.  But  it  may  also  occur  when  no  wave  of  contraction 
takes  place.  _  Its  occurrence  is  rendered  visible  by  the  movements  of  the 
tentacles  which  fringe  the  strip  and  are  much  more  sensitive  than  the  con- 
tractile tissue  of  the  strip  itself.  This  wave  of  stimulation  without  contraction 
passing  along  the  strip  will  cause  the  bell  to  contract  on  reaching  it,  provided 
there  is  a  marginal  ganglion  in  the  bell,  but  not  if  the  bell  is  paralysed.  The 
wave  of  stimulation  is  more  easily  excited  than  that  of  contraction,  so  that 
it  may  occur  from  stimuli  too  weak  to  excite  a  wave  of  contraction.  The 
passage  of  stimuli  along  the  strip  may  be  impeded  or  prevented  altogether  by 
compressing  the  strip,  by  making  transverse  incisions  into  it  so  as  to  narrow 
the  band  of  tissue  by  which  the  wave  is  transmitted,  or  by  injuring  the  tissue. 


chap,  iv.]     ACTION '  OF  DEUGS  ON  INVEETEBEATA.  Ill 

by  straining.  Sometimes  the  contraction  wave  may  be  blocked  by  the  injury 
before  the  stimulus  wave,  and  sometimes  the  stimulus  wave  may  be  blocked 
before  the  contraction  wave.  When  the  block  is  only  partial  it  frequently 
happens  that  two  or  three  waves  will  pass  along  the  strip  up  to  the  block 
without  being  able  to  cross  it,  but  after  a  long  time  their  effect  appears  to 
penetrate  so  that  a  wave  at  last  crosses  it. 

As  Gaskell  has  shown,  a  similar  occurrence  takes  place  in  the  frog's 
heart,  and  stimuli  proceeding  from  the  auricle  to  the  ventricle  may  also  be 
blocked  by  compression. 

The  influence  of  poisons  can  be  studied  either  upon  the  bell  containing' 
the  ganglia,  or  upon  this  marginal  strip. 

In  healthy  medusae  chloroform  first  arrests  the  spontaneous  movements 
of  the  bell.  When  now  irritated  it  answers  by  a  single  contraction,  instead 
of  by  a  series,  to  such  stimulation. 

After  the  bell  has  ceased  to  respond,  nipping  its  margin  causes  the  polyp 
to  contract. 

After  stimulation  of  any  part  of  the  bell  ceases  to  produce  response  in  any 
part  of  the  organism,  the  polyp  will  respond  to  stimuli  directly  applied  to  it. 
Nitrite  of  amyl  also  produces  effects  which  in  many  respects  are  similar  to 
those  of  chloroform.  There  are,  however,  certain  exceptions;  the  first  is 
that,  before  the  spontaneous  movements  are  abolished,  the  rhythm  becomes 
quickened,  and  the  strength  of  the  pulsations  is  diminished.  The  move- 
ments also  die  out  more  gradually  than  under  chloroform,  and  before  they 
entirely  cease  they  become  localised  to  the  muscular  tissue  close  to  the 
margin.  "When  the  dose  is  large,  spasmodic  contractions  are  produced  which 
obliterate  the  gradual  paralysing  action  of  the  drug. 

Caffeine  first  causes  an  increase  in  the  rate  of  pulsation,  and  diminishes  its 
strength  after  a  few  seconds.  This  condition  passes  off,  and  the  spontaneous 
movements  become  gradually  abolished.  They  still  remain  for  a  long  time 
sensitive  to  stimulation,  and  at  first  respond  by  several  feeble  contractions 
to  each  stimulus ;  afterwards  by  a  single  response ;  and  afterwards  they  do 
not  respond  at  all. 

As  medusas  paralysed  by  removal  of  the  ganglia  never  respond  to  a  single 
stimulus  with  more  than  a  single  contraction,  the  increased  number  of  con- 
tractions which  at  first  appear  after  the  application  of  the  stimulus,  are  pro- 
bably due  to  increased  reflex  irritability. 

Caffeine  causes  the  tentacles  and  polypi  to  lose  their  tonus,  and  become 
relaxed,  which  is  not  the  case  with  chloroform.     Medusas  anaesthetised  with  , 
chloroform  when  put  into  a  solution  of  caffeine  also  lose  their  tonus,  but  their 
irritability  is  restored,  though  their  spontaneity  is  not. 

The  effects  of  strychnine  differ  in  different  species  of  medusae.  In  Sarsia 
it  accelerates  the  rhythmical  contractions  which  occur  in  groups  separated  by 
intervals  of  quiescence.  This  quiescence  finally  becomes  continuous,  and 
during  it  the  animal  does  not  respond  to  irritation  of  the  tentacle,  but  does  so 
to  direct  muscular  stimulation. 

Veratrine  first  increases  the  number  and  power  of  the  contractions ;  after- 
wards it  diminishes  both. 

Digitalin  first  quickens  them,  then  renders  them  regular,  causes  persistent 
spasms,  and  produces  death  in  strong  systole. 

Atropine  causes  first  acceleration,  then  convulsions,  then  feeble  contractions, 
and  finally  death  in  systole. 

Nicotine  causes  violent  and  continuous  spasm,  with  numerous  minute 
rapid  contractions  superimposed  upon  it.  These  latter  soon  die  away,  leaving 
the  bell  in  strong  systole. 

After  spontaneous  movements  have  disappeared,  the  bell  no  longer 
responds  to  stimulation  of  the  tentacles,  but  responds  to  direct  stimulation. 

Alcohol  first  greatly  increases  the  rapidity  of  the  contractions,  so  much  so 
that  the  bell  has  no  time  to  expand  properly  between  them,  and  they  are  in 
consequence  feeble  and  gradually  die  out.  The  reflex  stimulation  shortly 
ceases  to  produce  any  effect,  but  muscular  irritability  is  longer  maintained. 


112  PHABMACOLOGY  AND   THERAPEUTICS,     [sect,  i.,. 

Cyanide  of  potassium  first  quickens  and  then  enfeebles  the  contractions ; 
spontaneous  movements  rapidly  cease,  and  the  bell  soon  becomes  irresponsive 
either  to  irritation  of  the  tentacles,  or  to  direct  irritation.  For  a  long  time 
after  it  has  become  irresponsive,  the  nervous  connections  between  the  tentacles 
and  polyp  remain  intact,  as  also  do  the  nervous  connections  of  these  organs 
with  all  parts  of  the  bell.  The  sensory  organs  are  therefore  not  paralysed  by 
this  drug. 

The  effects  of  poisons  on  medusae  were  localised  by  Eomanes  in  two  ways. 
One  way  was  to  divide  the  medusa  almost  into  two  halves,  connected  only  by 
a  narrow  strip  of  tissue.  These  halves  were  plunged  into  two  beakers  filled 
with  sea-water,  pure  in  one  and  poisoned  in  the  other.     The  connecting  strip 


Fig.  32.— Diagrammatic  representation  of  the  method  of  localising  the  action  of  poisons  on  medusa. 
One  vessel  contains  normal  sea-water  ;  another  contains  poisoned  sea-w&ter,  which  is  shaded  in 
order  to  distinguish  it. 

rested  upon  the  edges  of  the  beaker.  When  curare  was  employed  as  a  poison 
in  this  way,  it  was  found  to  have  an  action  similar  to  that  which  it  exerts  on 
mammals  :  apparently  paralysing  the  motor  nerves,  while  it  left  the  sensory 
nerves  capable  of  action.  Thus,  on  nipping  the  half  of  a  medusa  which  was 
plunged  in  the  curare  solution,  it  remained  absolutely  motionless,  while  the 
other  half  at  once  responded  by  a  peculiar  contraction  to  the  stimulus.  Here, 
also,  however,  just  as  in  mammals,  the  sensory  fibres  are  also  paralysed  by  a 
large  dose,  so  that  if  much  poison  be  used,  irritation  of  the  poisoned  part  will 
have  no  effect  either  upon  it  or  upon  the  unpoisoned  part.  "When  experiment- 
ing in  this  way  with  strychnine,  Krukenberg  found  that  the  excitability  of 
the  poisoned  part  was  increased,  so  that  when  he  touched  the  connecting  strip 
lightly  with  a  needle  no  effect  was  produced  on  the  unpoisoned  half,  but  the 
poisoned  half  responded  by  several  energetic  contractions.  Veratrine  had  a 
similar  action  to  that  of  curare,  so  that  irritation  of  the  poisoned  half  caused 
no  movement  in  it,  but  caused  movement  in  the  unpoisoned  half.  The  irrita- 
bility of  the  contractile  tissue  is  also  diminished  so  that  it  no  longer  reacts  so 
readily  in  the  poisoned  half  to  electrical  stimuli. 

Nicotine  appears  to  paralyse  the  ganglionic  structures  and  not  the  nerves. 

It  has  already  been  mentioned  that  the  rhythmical  movements  of  medusse 
depend  upon  the  ganglia :  when  these  are  all  cut  off  the  movements  cease, . 
but  if  only  one  be  left  the  movements  continue.  In  the  medusa  divided  into 
two  halves,  as  already  described,  it  is  evident  that  if  the  ganglia  are  removed 
from  one  half,  or  one  half  rendered  functionally  inactive  by  poison,  that  half 
will  still  continue  to  contract,  so  long  as  it  remains  connected  with  the  other 
half,  but  will  cease  to  move  when  it  is  completely  divided  from  the  half 
which  still  contains  ganglia.  The  effect  of  nicotine  is  such  as  one  would 
expect  if  the  poison  paralyses  the  ganglia,  for  it  is  found  that  when  one  half 
of  a  medusa  is  steeped  in  water  containing  nicotine,  both  halves  still  continue 
to  pulsate  rhythmically ;  so  soon  as  the  connecting  band  of  tissue  is  divided, 
the  poisoned  half  at  once  ceases  to  move,  while  the  other  half  continues  to 
pulsate. 

The  second  way  in  which  Eomanes  localised  the  action  of  poisons  on 
medusae  was  by  applying  them  to  a  strip  of  contractile  tissue.  He  found 
that  various  poisons  applied  to  the  strip,  or  injected  into  it,  caused  a  blockage 
of  contractile  waves,  preceded  by  a  progressive  slowing  of  the  rate  of  trans- 
mission along  the  poisoned  part.  Chloroform,  ether,  alcohol,  morphine, 
strychnine,  and  curare,  all  have  this  effect. 


chap,  iv.]    ACTION  OF  DEUGS  ON  INVEETEBEATA.  113 

General  Results. — The  most  marked  results  of  experiments 
on  medusse  are,  that  the  contractile  tissue  contracts  rhythmi- 
cally when  stimulated  by  ganglia.  It  ceases  to  do  so  when  the 
ganglia  are  removed  and  the  contractile  tissue  left  under  ordinary 
conditions,  hut  a  constant  stimulus,  either  chemical  or  electrical, 
applied  to  it  after  the  removal  of  the  ganglia,  will  cause  it  to 
beat  rhythmically  just  a's  if  the  ganglia  were  present.  This 
appears  to  show  that  the  rhythmical  contractile  power  is  a  func- 
tion of  the  contractile  tissue  and  not  merely  of  the  ganglia. 
Besides  its  power  of  contracting  once  on  the  application  of  a 
single  stimulus,  or  rhythmically  from  continued  stimulation,  the 
contractile  tissue  also  possesses  the  power  to  conduct  stimuli. 
This  is  seen  in  the  passage  of  the  contraction  wave  along  a  strip 
of  medusa  which,  on  reaching  the  bell,  causes  it  to  contract. 
When  two  contraction  waves  travelling  along  the  contractile 
strip  in  opposite  directions  meet  one  another  they  arrest  each 
other.  This  mutual  extinction  may  be  regarded  either  as  a 
process  of  inhibition  or  interference,  or  as  a  consequence  of  ex- 
haustion of  the  tissue  which  possibly  may  be  unable  to  contract 
twice  with  such  a  short  interval  between. 

The  power  of  the  contractile  tissue  to  transmit  stimuli  is 
diminished  or  destroyed  by  cutting  it  more  or  less  completely 
across,  by  compression,  by  stretching,  by  very  high  or  low  tem- 
peratures, and  by  poisons  such  as  chloroform,  morphine,  nitrite 
of  amyl,  caffeine,  strychnine,  curare,  and  indeed  almost  any 
foreign  substance  added  to  the  water  in  which  the  strip  is  im- 
mersed. 

There  are,  however,  two  conducting  channels,  along  which 
stimuli  may  be  transmitted ;  the  first,  already  mentioned,  is  the 
contractile  tissue;  the  second  is  the  nervous  tissue.  The 
passage  of  stimuli  along  the  second  is  rendered  evident  by  the 
movements  of  the  tentacles.  These  nervous  or  tentacular  waves 
and  the  contractile  waves  may  exist  either  together  or  separately. 
The  nervous  waves  are  excited  by  stimuli  which  are  too  weak  to 
excite  contraction  waves,  and  it  is  to  be  particularly  remarked 
that  when  this  is  the  case  they  only  travel  at  half  the  rate  at 
which  a  contraction  wave  travels,  although,  when  the  stimulus 
is  strong  enough  to  excite  a  contraction  wave  also,  both  the 
nervous  and  the  contractile  wave  travel  at  the  same  rate,  the 
nervous  one  being  a  little  ahead  of  the  other.  The  passage  of 
nervous  stimuli  may  also  be  diminished  or  completely  blocked 
by  section  or  compression  just  as  in  the  case  of  contraction  waves. 

The  transmission  of  stimuli  along  nerves  is  also  affected  by 
poisons.  It  appears  to  be  destroyed  by  anaesthetics,  though 
more  slowly  than  that  of  the  contractile  tissue.  The  ganglia  may 
be  paralysed,  e.g.  by  nicotine,  before  the  transmission  of  nervous 
stimuli  from  them  is  diminished.  The  contractile  tissue  alone 
may  be  paralysed. 


Ill     PHAEMACOLOGY  AND  THEKAPEUTICS.  [sect.!.* 


Action  of  Drugs  on  Mollusca. 

In  the  lameiiibranchlata,  instead  of  a  chain  of  ganglia,  as  in  the 
medusae,  we  have  three  pairs  of  ganglia  :  cerebral  at  the  mouth,  pedal  in  the 
foot,  and  parietal-splanchnic  supplying  the  bronchial  apparatus  and  viscera. 
The  heart  has  distinct  chambers,  but  apparently  consists  of  protoplasmic 
substance  without  distinct  nerves  or  ganglia.*  The  application  to  it  of  an 
interrupted  current  will  arrest  the  rhythmical  pulsation  and  cause  stoppage 
in  diastole.1  This  effect  is  prevented  by  atropine.  Warmth  up  to  104° 
quickens  the  heart ;  when  raised  higher  it  destroys  reflex  movement  in  the 
animal,  and  afterwards  arrests  the  heart  also.  Pure  water  without  salts 
quickly  paralyses  the  muscles  and  causes  death  in  salt-water  molluscs. 
Curare  in  small  doses  has  no  effect,  large  doses  quicken,  but  do  not  abolish 
movement,  and  do  not  affect  the  heart.  Strychnine  somewhat  stimulates 
movement,  and  may  cause  some  local  contractions,  but  never  any  general 
tetanus.  Nicotine  acts  in  a  similar  way,  but  in  large  doses  appears  to  para- 
lyse the  muscles  and  cause  death ;  it  also  appears  to  cause  contraction  ot 
the  vessels,  so  that  the  heart  becomes  more  bulky  and  beats  more  quickly. 
Veratrine  has  a  similar  action.  Digitalis  has  no  action,  excepting  when 
applied  to  the  heart  directly,  and  then  it  renders  the  beats  slower  and  some- 
times stops  them.  Antiarine,  like  digitalis,  has  no  general  action,  but  stops 
the  heart  if  applied  to  it  directly.  Muscarine  generally  causes  muscular 
contractions  in  the  body :  first  acceleration,  quickly  followed  by  retardation 
of  the  cardiac  beats.  Sulphocyanide  of  potassium  diminishes  reflex  action, 
but  has  little  effect  on  the  excitability  of  the  nerves.  A  small  dose  somewhat 
quickens  the  cardiac  action ;  a  large  dose  stops  the  heart  in  diastole,  and  if  it 
is  directly  applied  to  the  heart  the  stoppage  is  permanent. 

Action  of  Drugs  on  Ascidians. 

The  heart  in  ascidians  consists  of  a  tube  open  at  both  ends,  and  which,  by 
its  contraction,  drives  the  visceral  fluid  alternately  towards  the  viscera  and 
away  from  them.  Its  action  does  not  seem  to  depend  on  the  nervous 
ganglion  lying  between  the  oral  and  anal  sac,  or  indeed  upon  nervous 
influence  at  all. 

The  application  of  an  induced  current  causes  it  to  beat  for  some  time  in 
one  direction  instead  of  alternately,  but  does  not  arrest  its  pulsations.2  Ac- 
cording to  Krukenberg  it  is  not  affected  either  by  atropine  or  muscarine.  It 
is  paralysed  by  veratrine,  quinine,  and  strychnine :  these  poisons  rendering 
the  beats  gradually  weaker  and  more  irregular.  No  evidences  of  tetanus  are 
to  be  seen  from  the  action  of  strychnine.  The  mode  of  action  of  the  heart  is 
affected  by  helleborin  and  nicotine :  helleborin  increases  the  number  of  the 
advisceral  beats  while  nicotine  diminishes  them.  Camphor  and  strychnine 
have  possibly  an  action  in  this  respect  resembling  helleborin. 

Action  of  Drugs  on  Annulosa. 

In  annulosa  the  nervous  system  consists  of  ganglia  in  each  segment 
united  together  by  nervous  bundles.  These  bundles  in  general  appearance 
correspond  with  the  gangliated  cord  of  the  sympathetic  in  higher  animals. 
The  spinal  cord  is  absent :  we  might  therefore  expect  that  drugs  which 
act  specially  on  the  spinal  cord  in  vertebrates  would  not  have  the  same 


1  M.  Poster,  Pfliiger's  Archiv,  v.  191. 

*  Dew-Smith,  Proc.  Boy.  Soc,  March  18, 1875,  p.  336. 


chap,  iv.]    ACTION  OF  DEUGS  ON  INVEETEBEATA. 


115 


marked  action  on  annelida,  and  this  appears  to  be  the  case.  It  was  found  by 
Moseley  that  strychnine  had  no  action  on  cockroaches ; '  and  leeches,  when 
placed  in  water  containing  strychnine,  become  elongated  but  do  not  exhibit 
signs  of  tetanus.  Some  years  ago  I  noticed  that  ants  sprinkled  with  insect- 
powder  died  in  violent  convulsions,  and  it  occurred  to  me  that  possibly  sub- 
stances which  excite  movements  of  the  intestine  in  the  higher  animals  might 
have  a  somewhat  convulsant  action  on  invertebrates.  I  therefore  tried  the 
effect  of  oil  of  peppermint  on  ieeches,  and  it  produced  in  them  violent  excite- 
ment. This  appears  to  be  of  a  somewhat  convulsant  nature  :  the  animal  at 
first  flying  rapidly  hither  and  thither  through  the  water,  and  afterwards,  when 
it  becomes  quiet  and  nearly  exhausted,  there  is  a  constant  rhythmical  twitch- 
ing movement  in  the  body  which  appears  to  last  nearly  until  death.  But  if  my 
idea  had  been  correct,  all  carminatives  should  excite  convulsions  in  annulosa. 
This  is  not  the  case,  for  the  oils  of  peppermint,  caraway,  and  anise  have  no 
apparent  effect  on  black-beetles  other  than  that  of  making  them  sluggish. 

Chloroform,  ether,  and  other  substances  belonging  to  the  alcohol  group, 
act  as  anaesthetics  on  mammals,  temporarily  abolishing  the  functional 
activity  of  the  brain,  spinal  cord,  and  medulla.  On  annulosa  they  have  a 
similar  action,  although  Krukenberg 2  supposed  they  had  a  different  effect, 
coagulating  the  muscular  substance  and  rendering  it  stiff  and  hard  before 
affecting  the  nerves.      The  experiment  by  which   he   thought  this    was 


Fig.  33.— Krukenberg's  apparatus  for  investigating  the  action  of  chloroform,  &c.,  on  annifosa. 
a  is  a  shallow  vessel  containing  a  little  water.  6  is  a  beaker  containing  water,  saturated  with 
chloroform,  or  ether,  and  covered  with  a  piece  of  millboard  c,  in  which  are  two  holes.  Through 
these  holes  the  head  and  tail  of  a  leech,  d,  are  drawn  and  fastened  by  ligatures  held  by  two 
clamps,   e  is  a  bell-jar  covering  the  whole. 

proved  consisted  in  applying  chloroform  to  the  middle  part  of  a  leech 
while  the  two  ends  of  the  animal  were  protected  from  the  action  of  the 
vapour.  The  middle  part  then  became  stiff  and  rigid,  but  the  movements 
of  the  two  ends  of  the  animal  were  perfectly  co-ordinated,  so  that  its 
actions  were  that  of  a  single  animal  having  a  stiff  girdle  surrounding  its 
middle.  Ether  and  alcohol  had  a  similar  result.  The  co-ordination  of 
the  two  ends  showed  that  although  the  muscles  had  been  rendered  rigid 
by  chloroform,  the  nerves  which  passed  through  the  middle  part  of  the 
body  were  still  functionally  active.  When  the  middle  part  of  the  body  was 
coagulated  by  the  application  of  hot  water,  the  muscles  became  rigid  but 
the  nerves  were  also  destroyed,  and  the  movements  of  the  two  ends  of  the 
animal  were  no  longer  co-ordinated,  so  that  they  appeared  like  two  dis- 
tinct animals  connected  by  a  rigid  cylinder.  Luchsinger s  repeated  Kruken- 
berg's experiments,  and  found  that  although  the  muscles  were  affected  by 
the  chloroform,  yet  the  nervous  system  was  still  more  sensitive  than  the 
muscles. 


1  Moseley,  unpublished  experiment  made  in  C.  Ludwig's  laboratory. 

*  Krukenberg,  Vergleicliend.  physiologische  Sttidien,  Abtg.  I.,  p.  77. 

*  Luchsinger  und  Guillebeau,  PflUger's  Archill,  xxviii.,  p.  61. 

i  2 


116  PHAEMACOLOGY  AND  THERAPEUTICS,     [sect,  i.' 

Atropine  has  a  similar  action  to  chloroform,  ether,  and  alcohol,  on  the 
muscles  of  the  leech.  Veratrine  appears  to  some  extent  to  affect  the  muscles, 
30  that  after  contraction  they  relax  slowly.  It  appears  also,  however,  to 
affect  the  nerve-centres,  and,  according  to  Krukenberg,  paralyses  more 
especially  the  sensory  centres.  Camphor,  strychnine,  morphine,  caffeine, 
copper  sulphate,  and  mercuric  chloride  act  chiefly  on  the  nervous  system  of 
leeches,  although  they  also  affect  the  muscles  when  applied  for  a  length  of 
time.     Caffeine  renders  the  muscles  in  the  leech  also  rigid. 


117 


CHAPTEE  V. 
ACTION  OP  DKUGS  ON  MUSCLE. 

Action  of  Drugs  on  Voluntary  Muscle. 

In  the  bodies  of  animals  we  find  the  protoplasmic  masses  or  cells 
of  which  they  are  composed  variously  modified,  in  order  to  per- 
form special  functions. 

In  some  the  power  of  nutrition  is  chiefly  developed :  and 
this  we  find  in  glands.  In  others  the  power  of  contractility 
is  developed:  and  this  we  find  in  muscles,  striated  and  non- 
striated. 

In  the  course  of  special  development  towards  the  fulfilment 
of  a  particular  function,  the  protoplasm  of  the  muscular  cells 
undergoes  marked  changes.  But  it  must  always  be  borne  in 
mind  that  the  protoplasmic  elements  of  the  body,  however  dif- 
ferent from  one  another,  always  tend  more  or  less  to  retain  all 
the  functions  which  are  seen  in  an  organism  consisting  of  a 
single  cell,  a  reference  to  which  may  sometimes  throw  much 
light  upon  the  mode  of  life  of  the  more  highly  organised  tissues. 

In  amoebae  or  leucocytes  the  protoplasm  contracts  in  any 
direction  and  when  strongly  contracted  in  tetanus  they  become 
spherical. 

In  muscle  the  protoplasm  is  specially  modified  and  contracts 
chiefly  in  one  direction,  viz.  that  of  its  length,  and,  indeed,  it  is 
usually  assumed  that  muscular  fibre,  either  voluntary  or  in- 
voluntary, contracts  in  the  direction  of  its  length  only. 

But  the  probability  of  its  contraction  in  a  transverse  direction 
also  is  to  be  borne  in  mind,  and  there  are  some  phenomena 
which  it  is  very  hard  to  explain  except  on  the  supposition  that 
muscle  contracts  transversely  as  well  as  longitudinally.1 

We  distinguish  in  muscle  its  elasticity,  a  physical  property ; 
and  its  contractility,  a  vital  property. 

1  Thus  Weber  found  that  when  a  muscle  is  loaded  with  a  weight  too  great  for 
it  to  lift,  instead  of  shortening,  it  elongates.  The  usual  explanation  of  this  is  that 
the  elasticity  of  the  muscle  then  becomes  diminished ;  but  according  to  Wundt 
the  elasticity  is  not  changed.  If  we  suppose  that  stimulation  tends  to  make  the 
muscle  contract  transversely  as  well  as  longitudinally,  the  explanation  is  easy,  for 
in  this  case,  longitudinal  contraction  being  prevented,  the  transverse  contraction 
tends  to  elongate  the  muscle. 


118  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

The  word  elasticity  is  applied  to  the  tendency  of  the  body 
both  to  resist  change  of  its  form,  and  to  regain  it  when  this 
change  has  been  effected  :  so  that  ivory  may  be  taken  as  the 
type  of  a  very  strongly  elastic  body.  Indiarubber,  on  the  other 
hand,  is  regarded  as  a  feebly  elastic  body,  because  it  does  not 
strongly  resist  changes  of  form,  although  it  tends  very  strongly 
to  regain  its  original  form  after  such  changes.  It  is,  however, 
popularly  regarded  as  the  perfect  type  of  an  elastic  body.  In 
talking  of  the  elasticity  of  muscle,  confusion  is  apt  to  occur ;  it 
is  better,  then,  to  avoid  the  term  elasticity  and  to  use  the  words 
suggested  by  Marey — extensibility  and  retractility.  The  exten- 
sibility of  muscle  is  of  two  kinds — immediate  and  supplementary. 
When  a  weight  is  attached  to  it,  it  extends  considerably ;  this  is 
its  immediate  extensibility ;  it  then  goes  on  slowly  and  gradually 
lengthening  for  a  considerable  time,  and  this  is  supplementary 
.  extensibility.  When  the  weight  is  removed  the  retractile  power 
of  the  muscle  again  becomes  evident,  and  there  is  immediate 
retractility  and  supplementary  retractility,  the  muscle  at  once 
contracting  to  a  considerable  extent,  and  then  continuing  to  do 
so  slowly  and  gradually  for  some  time  afterwards. 

The  extensibility  of  a  muscle  is  increased  by  stimulation,  so 
that  if  a  weight  be  hung  on  a  muscle  while  it  is  contracted  in 
consequence  of  stimulation,  it  will  produce  a  greater  extension 
than  it  would  if  applied  to  the  same  muscle  in  a  state  of  rest ; 
and  if  a  muscle  be  loaded  with  a  weight  too  great  for  it  to  raise, 
stimulation,  instead  of  causing  contraction,  causes  elongation.1 
Heat  renders  the  muscle  less  extensible  and  more  retractile; 
cold  has  an  opposite  effect,  rendering  it  more  extensible  and  less 


Fig.  34.— Ehows  the  fiction  on  muscle  ot  caustic  &utia,  1  in  z.uuu,  once  renewed  in  25  minutes,  followed 
by  the  action  of  lactic  acid,  1  in  600,  once  renewed  in  25  minutes.    (Eruiitou  and  Cash.) 


Fig.  35.— Shows  the  action  on  muscle  of  caustic  potash,  1  in  2,6ou,  twice  renewed  for  13  minutes, 
succeeded  by  the  aotion  of  lactic  acid,  1  in  600,  for  18  minutes,  and  this  by  the  action  of  caustic 
potash  for  17'5  minutes.    (Ct  Fig.  60,  p.  132.)    (Brunton  and  Cash.) 

retractile.     Section  of  the  nerve  has  a  similar  effect  to  that  of 
cold.    Fatigue  increases  the  extensibility.     Alkalis  (potash  or 

1  Vide  footnote, ».  117. 


chap.  v.J        ACTION  OF  DEUGS  ON  MUSCLE.  119 

soda),   in   very  dilute  solutions,  diminish  extensibility;  dilute 
acids  (lactic  acid)  increase  it.    By  the  alternate  application  of 


Fig.  36.— Shows  the  action  01  caustic  potash,  1  in  1,600,  on  muscle  for  18  minutes,  succeeded  by  the 
action  of  lactic  acid  for  24  minutes.  1  is  the  contraction  of  normal  muscle ;  2,  3, 4,  contractions 
of  alkali-muscle ;  5,  6,  7,  contractions  of  acid-muscle  on  stimulation.    (Brunton  and  Cash.) 

alkalis  and  acids  the  muscle  may  be  made  to  yield  curves  which, 
■  when  recorded  on  a  very  slowly-revolving  cylinder,  are  similar  in 
form  to  the  normal  contraction  curve  recorded  on  a  rapidly- 
revolving  cylinder.1     Fig.  34. 

Irritability  of  Muscle. — In  order  to  ascertain  the  irrita- 
bility of  muscle  itself  or  the  readiness  with  which  it  responds 
to  various  stimuli  independently  of  the  nerves  within  it,  the 
muscle  is  first  jpoisoned  by  curare,  and  then  exposed  to  various 
conditions,  or  to  the  action  of  drugs.  The  muscle  thus  poisoned 
by  curare,  woorara,  woorali,  or  urari  (for  the  poison  has  all 
these  names),  is  much  less  sensitive  to  the  action  of  fara- 
daic  currents.  The  readiest  way  of  testing  its  excitability  is  by 
the  making  and  breaking  of  a  constant  current,  the  strength 
of  which  can  be  estimated  very  exactly  by  using  du  Bois  Bey- 
mond's  rheochord.  The  excitability  of  muscles  is  increased  by 
heat  and  diminished  by  cold.  It  is  increased  by  physostigmine 
and  diminished  by  most  poisons  which  paralyse  muscle.2 

Contraction.— "When  the  ends  of  the  muscle  are  not  kept 
apart  by  force  too  great  for  it  to  overcome,  and  it  is  stimulated 
by  heat,  mechanical  injury,  chemical  irritants,  or  electricity,  it 
contracts  and  then  relaxes. 

The  form  of  this  contraction  varies  according  to  the  species 
of  animal,  and  the  particular  muscle  tested. 

In  cold-blooded  animals,  as  a  rule,  the  contraction  is  slower 
than  in  warm-blooded  animals.  It  is  not  alike  in  all  the  muscles 
of  the  body  of  mammals.  Thus  in  the  rabbit  there  are  two 
kinds  of  muscles — red  and  white ;  the  white  muscles  contract 
more  quickly  and  relax  more  quickly  than  the  red  ones.  The 
muscle  usually  employed  in  experiments  is  the  gastrocnemius  of 
the  frog,  freshly  prepared,  with  the  nerve  and  end  of  the  femur 
attached  to  it. 

1  Brunton  and  Cash,  Phil.  Trans.,  1884,  p.  197. 

1  Harnack  and  Witkcrwski,  Arch.  f.  exp.  Path.  u.  Pharm.  v.  1876,  p.  402. 


120 


PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


The  femur  is  fixed  in  a  clamp,  and  the  lower  end  of  the 
muscle  is  attached  to  a  writing  lever  usually  loaded  with  a 
weight  (Fig.  37).     The  end  of  this  lever  writes  upon  a  revolving 


if 

i 

— 

Fig.  37. — Apparatus  for  registering  muscular  contraction.  It  consists  of  an  upright  stand  on  which 
two  horizontal  bars  may  be  moved  by  a  rack  and  pinion.  The  upper  bar  ends  in  a  clamp,  the 
lower  carries  a  delicate  lever,  the  part  near  the  hinge  being  of  metal,  and  the  part  beyond  of 
light  wood  tipped  with  quill  or  tinfoil,  a,  a,  wires  for  exciting  muscle ;  &,  muscle  ;  c,  writing 
lever.  In  the  figure  no  arrangement  is  shown  for  exciting  the  nerve,  and  for  the  sake  of  sim- 
plicity the  weight  is  shown  directly  under  the  muscle.  In  actual  experiment,  however,  the 
weight  should  be  applied  close  to  the  axle,  or  on  it,  so  as  to  lessen  oscillation  due  to  the  inertia 
of  the  lever. 

cylinder  (Fig.  38),  which  is  made  to  rotate  with  greater  or  less 
rapidity.  The  rate  of  revolution  is  usually  ascertained  by 
marking  the  time  upon  it  by  means  of  an  electro-magnet  (Fig. 
39)  communicating  with  a  clock  or  metronome,  or,  when  the 
revolution  is  quick,  with  a  large  tuning-fork  vibrating  100  times 
or  more  per  second.  "When  the  cylinder  is  not  in  motion  each  ■ 
contraction  of  the  lever  makes  a  straight  line  upon  it  (Figs.  40  a 
and  46) ;  when  the  cylinder  is  moving,  the  lever  describes  a 
curve  which  is  more  or  less  elongated,  according  to  the  rapidity 
of  the  cylinder's  rotation  (Figs.  40  and  41). 

Latent  Period  of  the  Muscle. — The  mechanical  energy 
developed  by  muscle  during  its  contraction  is  derived  from 
chemical  energy  liberated  by  changes  in  the  constituents  of  the 
muscle  itself.  These  are  of  the  nature  of  oxidation,  and  during 
them  oxygen  is  used  up,  and  carbonic  acid  is  liberated.  But 
the  oxygen  is  not  necessarily  present  either  around  the  muscle, 
or  in  the  blood  circulating  through  the  muscle  ;  it  is  stored  up  in 
some  loose  form  of  combination  within  the  muscle.1 

1  It  would  appear  that  this  force-yielding  substance,  or  muscle-dynamite,  as  we 
may  call  it,  is  not  present,  at  least  in  large  quantity,  in  the  muscles  in  a  form  in 
which  it  can  be  at  once  fired  off.  There  appears  rather  to  exist  a  substance  yielding 
it,  or  dynamogen,  which  may  be  looked  upon  as  corresponding  to  the  zymogen  of  the 
glands,  while  the  muscle-dynamite  may  be  regarded  as  corresponding  to  the  fer- 
ments of  glands.    Irritation  of  a  nerve  appears  both  to  liberate  muscle-dynamite 


chap,  v.]         ACTION  OP  DEUGS  ON  MUSCLE. 


121 


The  form  in  which  it  is  stored  up  has  been  compared  by  Lud- 
wig  to  gunpowder,  a  small  quantity  of  which  is  fired  off  at  each 
contraction. 

One  of  the  final  products  is  carbonic  acid ;  but  there  are 
intermediate  products,  one  of  them  being  sarcolactic  acid ;  and 
these  products  tend  to  cause  muscular  fatigue. 

Screw 


Brass  pin 


Framework 


Clockwork 


Fig.  38.— Revolving  cylinder  for  recording  movements.    The  screws  at  the  top  are  for  fixing  ttte-^ 
cylinder  in  position.    The  brass  pin  is  for  making  or  breaking  a  current  at  a  given  time  in  the 
revolution.    It  does  this  by  striking  against  a  small  key.    The  curve  is  described  by  the  lever, 
Fig.  37.    The  abscissa,  or  zero  line,  is  drawn  by  a  fixed  point,  and  serves  to  show  the  height  of 
the  contraction. 

When  they  are  washed  out  of  the  muscle  by  a  current  of 
blood,  or  of  simple  saline  solution,  the  fatigue  of  the  muscle  is 
removed ;  and  this  removal  is  effected  even  more  perfectly  when 
the  internal  oxidation  is  rendered  more  complete  by  adding  per- 
manganate of  potassium  to  the  solution,  or  by  the  addition  of 
minute  quantities  of  potash.  A  mere  trace  of  veratrine  has  also 
a  similar  effect  in  restoring  the  muscle  after  fatigue. 

and  to  explode  it,  if  we  may  so  term  it.  The  passage  of  a  constant  current  through 
the  muscle  appears  to  liberate  the  muscle-dynamite  from  the  dynamogen,  but 
causes  no  expulsion  except  at  the  moment  when  the  current  is  made  or  broken,  or 
its  strength  altered.  It  must  be  carefully  borne  in  mind  that  the  idea  of  a  muscle- 
dynamogen  is  at  present  simply  theoretical,  and  must  be  looked  upon  not  as  a  fact 
but  rather  as  a  means  of  remembering  facts.  According  to  A.  Schmidt,  however, 
the  contraction  and  relaxation  of  muscle  is  closely  connected  with  the  formation 
and  destruction  of  a  ferment. 


122  PHARMACOLOGY  AND   THERAPEUTICS,     [sect.  i. 

•  We  find  that  the  muscle  does  not  immediately  respond  to  a 
stimulus,  but  that  a  period  elapses  between  the  stimulus  and  the 
commencement  of  the  contraction,  which  is  on  the  average  about 
the  100th  of  a  second.     This  is  termed  the  latent  period. 

During  this  period  a  chemical  change  is  probably  going  on  in 
the  muscle,  and  it  is  evidenced  by  an  electrical  change  known 
as  the  negative  variation,  or  diminution  in  the  natural  current 
which  passes  from  the  longitudinal  to  the  transverse  section  of 
the  muscle. 

The  latent  period  is  altered  by  fatigue.  Loading  the  muscle 
shortens  the  latent  period,  until  the  load  is  just  sufficient  to 
extend  the  muscle.  An  increase  of  load  above  this,  lengthens 
the  latent  period.  Cold  lengthens  it ;  heat  shortens  it.  Small . 
doses  of  strychnine  or  veratrine  shorten  the  latent  period.  Large 
doses  of  strychnine  or  veratrine,  and  also  curare,  lengthen  it. 

Summation  of  Stimuli. — During  the  latent  period,  the 
stimulus  applied  to  a  muscle  excites  chemical  changes  which 
result  in  contraction ;  but  if  the  stimulus  be  very  small,  the 


Electro-magnet. 

(Indiarubber  thread  to  draw 
back  the  -writing-point  when 
released  by  the  magnet. 

Fio.  39.— Electro-magnet  (aiter~"Marey)  for  recording  time  on  a  cylinder.  When  used  to  record 
time,  the  current  is  made  and  broken  alternately  by  clockwork  or  by  a  tuning-fork.  It  may  be 
used  also  to  record  the  time  of  irritating  or  dividing  a  nerve,  or  of  injecting  a  poison,  &c. 

chemical  changes  may  be  so  slight  that  contraction  does  not 
occur.  If  the  stimulus,  however,  be  repeated  several  times,  the 
changes  which  it  induces  in  the  muscle  become  sufficient  to  pro- 
duce at  first  a  slight  contraction,  and  then  one  greater  and 
greater,  until  the  maximum  effect  is  produced — this  is  called 
summation.  It  occurs  not  only  in  voluntary  muscles,  but  in 
other  contractile  tissues,  such  as  those  of  the  medusa  (vide 
Fig.  30,  p.  110).  A  similar  phenomenon  occurs  also  in  the  heart, 
and  has  there  received  the  name  of  '  the  staircase.' 

Contraction  of  Muscle. — In  the  muscular  curve  we  notice 
(1)  the  rapidity  of  its  rise,  which  indicates  the  rapidity  of  con- 
traction of  the  muscle  ;  (2)  its  length,  indicating  the  duration  of 
contraction  ;  (3)  its  height,  indicating  power  of  contraction ;  and 
(4)  slowness  of  fall,  indicating  the  condition  of  extensibility. 

The  muscular  contraction  is  modified  by  numerous  conditions. 

One  of  these  is  the  strength  of  stimulus. 

The  stimulus  usually  applied  is  electricity,  as  its  strength  can 
be  more  easily  regulated,  and  it  does  not  destroy  the  muscle  so 
readily  as  mechanical  or  chemical  irritants. 


chap,  v.]         ACTION  OF  DEUGS  ON  MUSCLE. 


123 


"With  a  weak  current,  making  (closing)  has  no  action  on  the 
muscle,  but  breaking  (opening)  causes  contraction. 


Fig.  40. — Muscle  curves,  showing  the  different  appearances  they  present  according  to  the  rate  at 
which  the  recording  cylinder  revolves,  a  is  a  curve  with  a  very  slowly  revo'viug  cylinder ;  6,  e, 
and  d  are  curves  with  increasing  speed  of  rotation,  c  is  written  with  a  lever  pointiug  in  the 
opposite  direction  from  that  with  which  a  and  b  are  recorded,  and  the  curve  therefore  inclines 
to  the  other  side. 

A  moderate  current  gives  contraction  both  in  making  and 
breaking,  but  that  of  making  is  comparatively  small  (Fig.  41). 
With  a  strong  current  no  difference  is  observed. 


Fig.  41. — Shows  effect  of  making  and  breaking  shocks.  These  are  normal  muscle  curves  with  a 
still  quicker  rotating  cylinder  than  in  Fig.  40a*.  The  first  is  caused  by  irritating  the  muscle  by 
making  (closing)  a  constant  current,  and  the  second  by  breaking  (opening)  it. 


The  more  intense  the  stimulus,  the  higher  and  longer  is  the 
curve.    The  increase  in  height  is  shown  in  Fig.  42. 


Fig.  42.— Tracing  of  the  contractions  of  a  muscle  with  stimuli  of  varying  strength.  The  numbers 
indicate  the  distance  in  centimetres  of  the  secondary  from  the  primary  coil  in  the  induction 
apparatus.    As  and  Des  indicate  the  ascending  and  descending  direction  of  the  current. 

Cold  renders  contraction  slower,  lower,  and  more  prolonged 
(Pig.  48  6). 

Heat  renders  it  quicker,  higher,  and  shorter  (Fig.  43  a). 

Fatigue. — Fatigue  makes  the  ascent  slow,  the  height  less, 
and  the  descent  slow  (Fig.  44). 

Exhaustion  of  the  animal  has  a  similar  action ;  and  dilute 
acids  applied  to  the  muscle  produce  the  same  effect  (Fig.  36). 


124  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  r. 

The  effect  of  fatigue  is  probably  due  in  a  considerable  mea- 
sure to  the  accumulation  of  acid  products  of  muscular  waste. 


Fia.  43. — Effeot  of  heat  and  cold.    In  a  the  muscle  has  been  artificially  warmed,  and  in  b  it  has 

been  cooled. 

When  these  are  washed  out  by  passing  a  weak  solution  of 
chloride  of  sodium  through  the  vessels  of  the  muscle,  or  partially 
removed  by  kneading,  it  regains  to  a  great  extent  its  normal 
power  of  contraction. 


Fig.  44 Effect  ol  fatigue. 

Oxidising  agents,  such  as  permanganate  of  potassium,  added 
to  the  salt  solution,  increase  its  power,  and  restore  the  muscle 
even  more  quickly  and  completely.1 

Deprivation  of  blood  has  a  similar  action  on  the  muscle  to 
fatigue ;  and  free  circulation  of  blood  tends  to  remove  the  effects 
Of  fatigue. 

Contracture. — When  the  stimulation  is  exceedingly  strong, 
the  relaxation  after  contraction  may  become  very  slow,  and  the 
descent  of  the  curve  may  be  divided  into  two  parts.  At  first  it 
descends  for  a  short  time  pretty  quickly,  and  then  falls  very 
slowly  indeed.  This  long  contraction  of  the  muscle  is  known  as 
contracture.  It  is  very  strongly  marked  in  muscles  poisoned  by 
veratrine  or  barium.  It  occurs,  though  to  a  less  extent,  in 
muscles  poisoned  by  salts  of  calcium  and  strontium,  by  ammonia, 
and  by  the  chloride,  iodide,  nitrite,  nitrate,  and  cyanide  of 
ammonium.2 

The  cause  of  contracture  is  not  known ;  it  is  considered  not 
to  be  a  tetanic  contraction,  because  unlike  an  ordinary  tetanised 
muscle  it  does  not  give  rise  to  secondary  tetanus  in  another 
frog's  muscle,  when  the  nerve  of  the  latter  is  placed  upon  it.  It 
is,  however,  an  active  contraction,  not  a  mere  alteration  in  the 
elasticity  of  the  muscle  preventing  its  relaxation ;  for,  as  Fick 
and  Boehm  have   shown,   a  much  greater  amount  of  heat  is 

1  Kroneoker,  Ludwig's  Arbeiten,  1871,  p.  183. 
*  Bruntor.  and  Cash,  Proc.  Boy.  Soc,  1883. 


chap,  vj         ACTION  OF  DEUGS  ON  MUSCLE.  125 

developed  during  the  long-continued  contracture  than  in  an 
ordinary  contraction.  Sometimes,  and  indeed  not  unfrequently, 
the  contracture,  instead  of  consisting  of  a  single  prolonged  con- 
traction, appears  in  the  form  of  a  prolonged  contraction  added 
on  to  an  ordinary  contraction  before  relaxation  has  had  time  to 
occur.  This  gives  rise  to  a  peculiar  hump  in  the  curve,  as  is 
well  seen  in  the  middle  curve  in  Fig.  49.  This  appears  to  show 
that  the  contracture  is  really  a  double  phenomenon,  like  the  two 
contractions  observed  after  a  single  stimulation  in  the  muscle  of 


Flo.  45.— Secondary  contraction  in  the  muscle  of  a  crayfish.  The  thick  part  of  the  lower  line  shows 
the  time  during  which  the  muscle  was  irritated  fay  a  tetanising  current.  It  will  be  noticed  that 
the  secondary  contraction  occurs  after  the  irritation  has  ceased,  and  after  the  tetanus  Caused  by 
it  has  relaxed.  It  is  not  a  simple  continuous  rise,  but  exhibits  several  wares  indicative  of  a 
kind  of  rhythm.    (After  Bichet.) 

the  crayfish  by  Eichet  (Fig.  45).  How  far  the  contracture  may 
depend  upon  irritation  of  the  muscle  by  its.  own  current  has  yet 
to  be  determined. 

Tetanus. — If  instead  of  a  single  stimulation  a  number  of 
stimuli  rapidly  succeeding  each  other  are  applied  either  directly 
to  the  muscle  itself  or  to  its  motor  nerve,  we  get,  in  place  of  a 
single  contraction,  a  continued  contraction  or  tetanus.  As  this 
is  due  to  a  fresh  contraction  of  the  muscle  occurring  before  the 
previous  one  has  had  time  to  relax,  it  is  evident  that  the  number 
of  stimuli  requisite  to  produce  this  will  vary  with  the  length  of 
each  single  contraction  in  a  muscle.  Thus  in  the  muscles  of  the 
tortoise,  which  contract  and  relax  very  slowly,  tetanus  may  be 
produced  by  3  stimuli  per  second,  while  in  the  white  muscles  of 
rabbits  20  may  be  necessary,  and  in  some  muscles  of  birds  70 
stimuli  per  second  are  insufficient.  It  has  been  said  that  with 
as  rapid  stimuli  as  250  per  second  the  tetanus  ceases,  and  after 
a  single  initial  contraction  a  muscle  goes  to  rest  just  as  if  a  con- 
stant instead  of  an  interrupted  current  had  been  used.  Kro- 
necker  and  Stirling  have  shown  that,  with  no  less  than  22,000 
interruptions  per  second,  tetanus  is  still  obtained ;  but  when  such 
extremely  rapid  stimuli  are  applied,  the  muscle  still  contracts 
about  the  ordinary  rate  of  20  per  second ;  and  this  is  also  the 


126  PHAEMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

case  when  chemical  stimuli  are  applied  to  the  nerve,  or  when  the 
muscle  is  irritated  by  the  nerve-centres,  either  voluntarily  or  by 
artificial  stimuli  applied  to  them.  It  seems  therefore  probable 
that  the  number  of  contractions  of  the  muscles  in  tetanus  are 
not  due  to  the  number  of  stimuli  sent  down  from  the  nerve 
centres,  but  that  the  rate  is  determined  either  by  the  ends  of  the 
nerve  in  the  muscle  or  by  the  muscle  itself.1 

The  form  of  a  tetanus  curve  may  be  modified  very  consider- 
ably by  the  action  of  drugs :  thus  substances  which  diminish 
the  contractile  power  of  muscle  cause  the  tetanus  curve  to  fall 
very  rapidly  notwithstanding  the  continued  application  of  stimuli 
either  to  the  muscle  itself  or  to  its  nerve  (vide  Ammonia). 

Muscular  Poisons. — We  may  distinguish  several  groups  of 
muscular  poisons,  but  at  present  the  classification  is  difficult, 
and  the  division  into  six  groups  based  on  that  of  Kobert,  which  I 
have  adopted,  although  it  possesses  some  advantages,  is  far  from 
satisfactory,  and  can  only  be  regarded  as  temporary. 

Geoup  I. — Leaves,  the  irritability  of  the  muscle  unaffected,  but 
diminishes  the  total  amount  of  work  it  is  able  to  do. 

Group  II. — Diminishes  the  excitability  of  the  muscle  as  well  as 
its  capacity  for  work. 

Group  III. — Diminishes  the  capacity  for  work,  and  produces 
majked  irregularity  in  its  excitability. 

Group  IV. — Alters  the  form  of  the  muscular  curve. 

Group  V. — Increases  the  excitability. 

Group  VI.- — Increases  the  capacity  for  work. 


Fig.  46.— Tracings  showing  the  gradual  loss  of  contractile  power  from  fatigue  in  a  normal  muscle, 
a,  and  in  one  poisoned  by  carbolio  acid,  6.  Bach  section,  V—l',  4>c,  shows  the  contractions  in 
one  minute.    (After  Gies.) 

The  poisons  in  Group  I.  do  not  alter  the  muscle  curve,  so 
that  if  the  action  of  the  poison  were  tested  by  a  single  contrac- 
tion only,  it  would  be  supposed  that  the  muscle  was  unaffected ; 
they  lessen,  however,  the  amount  of  work  which  the  muscle  can 
yield. 

The  amount  of  work  is  estimated  by  the  weight  which  a 
muscle  raises  multiplied  into  the  number  of  times  it  is  lifted 
and  the  height  it  is  raised  each  time.     These  are  ascertained  by 

1  Wedenskii,  Archivf.  Anat.  u.  Physiol.  Phys.  Abthlg.  1883,  p.  325. 


chap,  v.]         ACTION  OF  DEUGS  ON  MUSCLE.  127 

registering  the  contractions  on  a  slowly  revolving  drum,  as  in 
Fig.  46,  which  shows  the  rapid  exhaustion  of  a  muscle  poisoned' 
by  carbolic  acid  as  compared  with  a  normal  one.  The  rapid 
exhaustion  of  muscles  may  also  be  observed  in  the  form  of  the 
tetanus  curve  which,  under  the  influence  of  such  poisons,  falls 
much  more  rapidly  in  height  than  that  of  the  normal  muscle. 

This  group  contains  a  number  of  drugs  having  an  emetic 
action.1  These  are :  apomorphine,  asclepiadine,  cyclamine,  del- 
phinine,  sanguinarine,  and  saponine,  copper,  zinc,  and  cadmium. 
Antimony  has  a  somewhat  similar  action,  but  only  in  large  doses, 
and  after  a  great  length  of  time.  Arsenic,  platinum,  and  pro- 
bably mercury,  act  in  the  same  way  as  antimony.2  Tin,  nickel,8 
cobalt,3  manganese,2  aluminium,  and  magnesium,  have  little  or 
no  action  on  muscle.  Large  doses  of  iron  are  nearly  as  powerful 
as  arsenic,  but  in  small  doses  it  rather  increases  the  amount  of 
work  the  muscle  can  do. 

Carbonic  oxide  at  the  atmospheric  pressure  does  not  affect 
muscular  contractility,  but  abolishes  it  at  a  pressure  of  five 
atmospheres. 

Perhaps  we  may  take  as  a  subdivision  of  this  group  those 
poisons  which  lessen  the  contractile  power  of  the  muscle  without 


Pitt.  47. — (After  Harnack.)  Shows  the  action  of  lead  on  muscle,  a  shows  the  contraction  of  a  normal 
muscle  after  eighty  stimulations ;  &,  the  irregular  contractions  of  a  muscle  poisoned  by  lead 
after  ten  to  fifty  stimulations ;  c  shows  the  slow  relaxation  of  the  muscle  after  contraction  in  a 
muscle  poisoned  by  lead  after  numerous  stimulations. 

altering  its  irritability.  When  a  muscle  poisoned  by  one  of  these 
is  stimulated,  it  may  contract  quite  as  readily  as  a  normal 
muscle,  provided  the  weight  that  it  has  to  raise  is  but  slight, 
but  it  cannot  raise  such  a  heavy  weight  as  a  normal  muscle. 
This  is  tested  by  loading  it  with  a  given  weight,  and  the  slightest 
contraction  is  ascertained  by  adjusting  the  lever  of  the  myograph 
in  such  a  way  that  if  raised  in  the  very  least  it  breaks  a  connec- 
tion in  an  electrical  current  and  causes  a  bell  to  ring.  By  this 
means  contractions  quite  imperceptible  to  the  eye  are  readily 
appreciated.  Digitalis  has  an  action  of  this  sort,  as  I  found  in 
some  experiments  carried  on  under  the  direction  of  Professor  J. 
Eosenthal  in  1868,  but  not  published. 

Group  II.  contains  salts  of  potassium,  lithium,  ammonium, 

1  Harnack,  Archie  f.  exp.  Path.  u.  Pharm.,  Bd.  ii.  p.  299,  and  iii.  p.  44. 

*  Kobert,  Arch.  f.  exp.  Path.  u.  Pharm.,  Bd.  xv.  p.  22,  and  xvi.  p.  361. 

*  Anderson  Stuart,  Journ.  of  Aruxt.  and  Physiol.,  vol.  xvii.  p.  89. 


128  PHAKMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

quinine,  cinchonine,  oil  of  mace,  alcohol  in  large  doses,  chloro- 
form, &c. 

Chloral,  chloroform,  and  ether  also  belong  to  this  group,  but 
they  might  also  be  reckoned  as  belonging  to  Group  IV.,  for  they 
slow  the  ascent,  lessen  the  height,  and  prolong  the  descent  of  the 
curve.     Curare  has  a  similar  action. 

It  is  usually  stated  that  curare,  while  it  paralyses  motor 
nerves,  leaves  the  excitability  of  the  muscles  unaffected,  but  this 
appears  not  to  be  quite  correct,  for,  when  very  weak  currents  are 
employed,  the  muscle  loses  its  excitability  by  them  before  the 
nerve,  and  the  contractions  of  the  muscle  at  the  same  time 
become  unequal.  It  is  perhaps  not  yet  perfectly  certain  how  far 
these  appearances  are  due  to  the  curare,  and  how  far  to  the 
gradual  death  of  the  muscle.1 

Group  III.  contains  poisons  of  which  lead  is  a  typical 
example.  These  poisons  cause  the  muscular  contractions  to  be- 
come very  unequal,  although  the  stimuli  are  equal  and  regular. 
Emetine  and  cocaine  have  a  similar  action  to  lead.  This 
action  is  probably  due  only  to  the  gradual  death  of  the  muscle. 
It  is  produced  also  by  ptomaines,  and  it  may  occur  in  muscles 
which  are  simply  dying  without  being  poisoned  at  all.2 

Group  IV.  contains  poisons  which  alter  the  form  of  the  curve 
to  a  marked  extent. 

The  action  of  veratrine  is  very  peculiar :  it  does  not  lessen 
the  rapidity  of  contraction,  and  even  increases  the  height  of  the 
curve,  but  it  prolongs  the  descent  to  an  enormous  extent. 


Fig.  48.— Tracing  of  the  contraction  curve  of  a  muscle  poisoned  by  veratrine,  showing  enormous 
prolongation  of  the  contraction,  the  recording  cylinder  making  many  complete  revolutions 
before  the  muscle  is  completely  relaxed. 

This  action  of  veratrine  is  most  marked  at  moderate  tem- 
peratures. 

It  is  much  diminished,  and  sometimes  entirely  removed,  by 
cold ;  and  it  disappears  also  when  the  temperature  of  the  muscle 
is  considerably  raised.  When  the  muscle  which  has  been  cooled 
or  heated  is  again  brought  back  to  a  moderate  temperature,  the 
contracture  sometimes  returns,  but  occasionally  does  not,  the 

1  Marey,  Travaux  du  Laboratoire,  1878,  p.  157. 
»  Mosso,  Les  Ptomaines,  Turin,  1883. 


chap,  v.]         ACTION  OF  DEUGS  ON  MUSCLE. 


129 


effect  of  veratrine  on  the  muscle  appearing  to  be  sometimes,  but 
by  no  means  always,  destroyed  by  the  heat  or  cold  to  which  the 
muscle  has  been  exposed.1 

The  result  of  this  exceedingly  prolonged  contraction  is  that  a 
frog  poisoned  with  veratrine  is  able  to  jump  with  considerable 
power,  but  the  extensor  muscles,  by  which  the  movement  is 
executed,  remain  contracted  instead  of  relaxing.  The  animal 
•  therefore  lies  extended  and  "stiff,  and  is  only  able  very  slowly  to 
draw  its  legs  up  towards  the  body.  After  they  have  been  drawn 
up,  the  flexors  in  their  turn  remain  contracted  for  a  while,  and 
so  the  animal  is  unable  to  jump  until  some  time  further  has 
elapsed. 

Another  remarkable  point  about  the  action  of  veratrine  on 
f  muscle  is,  that  although  a  single  contraction  lasts  so  long  as 
seriously  to  interfere  with  the  power  of  co-ordinated  movement, 
jet,  if  the  muscle  is  made  to  contract  a  few  times  in  rapid, 
succession,  the  effect  of  the  veratrine  disappears,  and  it  again 
:  acts  normally.  After  a  short  rest  the  effect  of  veratrine  again 
,  reappears.     . 

A  similar  action  to  that  of  veratrine  is  exerted  by  salts  of 
.  .barium,  which,  when  locally  applied,  cause  the  muscle  to  describe 


,  Fig.  49.— Tracing  of  the  contraction  curves  of  a  muscle  poisoned  by  veratrine,  showing  the 
peculiarly  elongated  curve  at  a  moderate  temperature,  and  its  restoration  nearly  to  the  normal 
.  by  cooling  and  heating. 

a  curve  resembling  that  of  veratrine,  not  only  in  its  form,  but  in 
the  alterations  produced  by  temperature  and  in  its  temporary 
disappearance  after  repeated  contractions.  A  similar  action 
is  exerted  also,  though  to  a  less  extent,  by  strontium  and 
calcium.  Salts  of  potassium  may  at  first  increase  the  height 
of  contraction,  but  afterwards  both  moderate  and   large   doses 

1  Brunton  and  Cash,  Joum.  of  Physiol.,  vol.  iv.  p.  1,  and  Centralblatt  f.  d.  med. 
Wiss.,  1S83,  No.  6. 


130  PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  7. 

shorten  the  muscular  curve,  and  lessen  its  height,  so  as  finally 
to  abolish  its  contractile  power  altogether.  When  applied  to  a 
muscle  poisoned  by  veratrine,  barium,  strontium,  or  calcium, 
salts  of  potassium  remove  the  excessive  prolongation  of  the  con- ' 
traction  which  these  drugs  occasion,  and  "restore  the  muscular 
curve  again  to  its  normal.1 

Although  veratrine  alters  the  form  of  the  muscular  curve 
so  greatly,  it  does  not  (excepting  in  large  doses)  paralyse  the 
muscle,  so  that  when  a  poisoned  muscle  is  made  to  contract  at 
regular  intervals  for  a  length  of  time,  it  is  able  to  do  as  much 
work  as  a  normal  one. 

Nearly  allied  to  this  is  another  group  of  muscular  poisons, 
some  of  which  have  already  been  mentioned  as  a  sub-division  of 
Group  I.  It  contains :  digitalin,  digitalein,  digitaleresin,  digitoxin, 
toxiresin,  scillain,  helleborein,  oleandrin,  adonidin,  neriodorin, 
and  neriodorein.  Tanghinia,  thevetin,  and  frynin,  or  toad 
poison,  probably  also  belong  to  this  class. 

These  drugs  do  not  lessen  the  irritability  of  muscle,  but 
appear  to  alter  somewhat  the  form  of  the  muscle  curve,  some- 
what in  the  same  way,  but  to  a  less  extent  than  substances  of 
the  veratrine  group.  Some  of  them  when  applied  in  a  concen-  • 
trated  form  directly  to  the  muscle  cause  a  condition  of  rigor. 
This  is  especially  the  case  with  caffeine  and  digitalin.  This  rigor 
is  well  marked  in  the  rana  temporaria,  and  only  to  a  compara- 
tively slight  extent  in  the  rana  esculenta.  Although  caffeine  in 
concentrated  solution  produces  rigor  mortis  in  the  muscle,  yet  in 
very  dilute  solutions  it  is  a  muscular  stimulant,  and  as  such  is 
included  in  the  sixth  group. 

Group  V.  contains  physostigmine,  which  increases  the  ex- 
citability of  muscle  to  slight  stimuli,  but  does  not  increase  the 
amount  of  work  it  can  do ;  on  the  contrary,  in  large  doses  it 
diminishes  it. 

Group  VI. — Poisons  belonging  to  this  group  in  small  doses 
increase  muscular  work,  and  cause  the  muscle  to  recover  rapidly 
after  exhaustion.  Greatin  has  this  power  to  a  great  extent;  - 
hypoxanthin  has  it  also,  though  less  powerfully.  The  effect  of 
these  substances  is  very  interesting,  because  they  are  products 
of  muscular  waste.  They  also  occur  in  beef-tea,  and  their  action 
appears  to  show  that  beef-tea  assists  muscular  power,  as  well  as 
acts  as  a  nervous  stimulant. 

Other  members  of  this  group  are  caffeine  and  glycogen: 
these  have  great  power  to  increase  muscular  work.  The  relation 
of  caffeine  to  hypoxanthin  is  very  interesting.  Xanthin,  which 
is  another  substance  derived  from  muscles,  differs  from  hypo- 
xanthin in  containing  one  atom  more  oxygen.  Theobromine,  the 
active  principle  of  cocoa,  is  dimethylxanthine ;  and  caffeine,  the 

1  Brunton  and  Cash,  Proc.  Roy.  Soc,  1883- 


chap,  v.]         ACTION   OP  DEUGS  ON  MUSCLE.  131 

active  principle  of  tea  and  coffee,  is  trimethylxanthine.  The 
restorative  effects  of  beef-tea,  coffee,  tea,  and  cocoa  have  long 
been  recognised  empirically,  although  their  action  could  not  be 
explained.  It  now  seems  not  at  all  improbable  that  it  may  be 
partly  due  to  their  restorative  effect  on  the  muscle. 

Massage. — The  effect  of  kneading  a  muscle  so  as  to  remove 
the  waste  products  from  it  is  very  extraordinary. 

When  the  muscles  of  an  uninjured  frog  are  stimulated  to 
contraction  by  the  rhythmic  application  of  maximal  induction 
currents  until  they  are  exhausted  and  no  longer  contract,  knead- 
ing them,  or  massage,  restores  their  contractility  so  that  their 
contractions  are  nearly  as  powerful  as  at  first,  while  simple  rest 
without  massage  has  very  little  restorative  effect.  In  man  also, 
while  a  rest  of  fifteen  minutes  after  exhausting  labour  had 
very  little  restorative  action,  massage  during  the  same  period 
increased  double  the  work  that  could  be  done.  Massage  has  a 
similar  action  to  very  complete  and  perfect  circulation  through 
the  muscle,  in  removing  the  waste  products  and  restoring  its 
power.1 

Propagation  of  the  Contraction  Wave  in  Muscle. — When 
a  muscle  is  irritated  at  one  point,  the  contraction  wave  which 
occurs  at  that  point  is  conducted  along  the  muscle  in  both 
directions. 

This  contraction  wave,  like  that  which  occurs  in  the  con- 
tractile tissue  of  the  medusa,  is  independent  of  the  nervous 
system.  The  completeness  with  which  it  is  conducted,  and  the 
quickness  with  which  it  subsides  at  each  point,  are  closely  con- 
nected with  the  rapidity  of  the  conduction,  and  they  are  also 
injuriously  affected  by  anything  which  impairs  it.  It  diminishes 
during  the  death  of  the  muscle,  and  it  is  lessened  also  by 
fatigue,  by  cold,  and  by  injury,  such  as  excessive  stimulation. 
Certain  poisons  also  lessen  it,  as  cyanide  of  potassium,  veratrine, 
and  upas  antiar.2 

Heat  increases  the  rapidity  of  the  conduction. 

Rhythmical  Contraction  of  Muscle. —  Ehythmical  con- 
traction is  frequently  regarded  as  a  function  of  involuntary 
muscular  fibre  only ;  this,  however,  is  not  the  case,  for  it  is 
observed  also  in  voluntary  muscles.  Ehythmical  contraction 
of  involuntary  muscle  is  seen  in  the  trachea,3  and  is  well 
marked  in  the  heart  and  blood-vessels.  It  is  very  distinct 
in  the  intestines  and  bladder,  and  becomes  still  more  marked 
after  the  influence  of  the  central  nervous  system  has  been 
destroyed.  In  the  case  of  the  sphincter  ani,  for  example,  the 
rhythm  is  strong  and  regular,  especially  after  the  nerves  have 

1  Zabludowski,  Central,  f.  d.  med.  Wiss.,  1883,  No.  14,  p.  241. 
1  Aeby,  XJntersuchungen  aber  die  Forlpflanzungsgeschwindigkeit  der  Reizungen 
der  quergestreiften  Muskclfaser.    Braunschweig,  1862,  p.  52. 
3  Honvath,  Pfliiger's  Archiv,  1875,  vol.  xiii.  p.  508. 

k  2 


132 


PHAEMACOLOGY   AND   THEEAPEUTICS.      [sect.t 


been  divided  and  the  muscle  subjected  to  some  mechanical 
distension  by  tbe  introduction  of  the  finger. 

In  voluntary  muscle  the  tendency  to  large  rhythmical  pul- 
sations is  slight,  although  we  see  rapid  contractions  occurring 
in  tetanus. 

The  number  of  impulses  sent  down  to  the  muscles  along  the 
motor  nerves,  from  the  spinal  cord,  is  about  10  per  second  in 
the  dog.  If  more  numerous  impulses  are  sent  down  from  the 
cerebral  cortex,  or  corona  radiata,  or  if  more  numerous  stimuli 
are  applied  to  the  spinal  cord  itself,  summation  appears  to  occur 
in  the  cells  of  the  spinal  cord,  and  only  10  impulses  per  second 
are  sent  out.1 

From  the  observations  of  Wedenskii,  that  irritation  of  the 
motor  nerve  of  a  muscle  by  exceedingly  rapid  stimuli  still  pro- 
duces the  same  number  of  contractions  in  the  muscle,  it  seems 
probable  that  this,  rate  of  contraction  is  due  to  the  constitution 


Fio.  50.— Tracing  of  the  contraction  curve  of  a  muscle  poisoned  by  veratrine  and  exposed  to  a  high 
temperature.  The  poison  tends  to  cause  prolonged  contraction,  and  the  high  temperature  to 
cause  rapid  relaxation  of  the  muscle.  The  result  is  a  somewhat  rhythmical  spontaneous  con- 
traction.   The  muscle  was  only  irritated  at  the  very  beginning  of  the  first  contraction. 

either  of  the  muscle  itself,  or  of  the  nerve-endings  within  it. 
Under  certain  circumstances,  however,  the  voluntary  muscle 
may  be  made  to  contract  with  a  slow  rhythmical  movement  of 
considerable  extent,  and  closely  resembling  that  of  involuntary 
muscular  fibre. 

Thus  voluntary  muscle  treated  by  veratrine  tends  to  renjain 
contracted  for  a  length  of  time  like  an  involuntary  muaole: 
heat  has  a  tendency  to  cause  its  relaxation,  and  sometimes,,  as 
is  seen  in  the  accompanying  figure  (Fig.  50),  these  contending 
influences  produce  in  the  voluntary  muscle  a  tendency  to  marked 
rhythmical  contraction. 

A  still  more  remarkable  phenomenon  has  been  noticed  by 
Kuhne,2  who  finds  that  when  the  uninjured  sartorius  of  a  frog 
is  placed  in  a  solution  of  5  grammes  NaCl,  and  2-5  grammes  of 
common  alkaline  crystallised  phosphate  of  sodium  in  a  litre  of 


1  Horsley  and  Schafer,  Proc.  Roy.  Soc,  vol.  xxxix.  p.  40G. 
=  Unters-uchungen  cms  dem  Phr/siologisclien  Institute  der  Universitttt  Heidek 
berg.    Sonderabclruck,  1879,  p.  16. 


chap,  v.]         ACTION  OF  DEUGS  ON  MUSCLE.  133 

water,  it  begins  to  contract  at  once,  and  after  it  has  been  trans- 
versely divided  it  beats  with  the  regularity  of  the  heart. 

The  effect  of  various  substances  on  the  rhythmic  action  of 
muscle  treated  in  this  way  has  been  investigated  by  Biedermann. 
He  finds  that  the  best  fluid  for  the  sartorius  is  5  grammes 
NaCl,  2-2"5  grammes  of  Na2HP04,  -04--05  gramme  of 
Nia2C03.  A  low  temperature,  not  rising  above  10°  C,  is 
best.  The  lower  the  temperature  the  slower  is  the  rhythm  and 
the  more  extensive  the  contraction.  Heat  quickens  the  rhythm 
and  lessens  the  contraction.  At  about  18°  to  20°  C.  the  con- 
tractions become  rapid  and  indistinct.  When  caustic  soda  is 
used  instead  of  carbonate,  the  effect  is  similar,  but  the  muscle 
dies  much  more  quickly.  Potassium  carbonate  and  other 
potassium  salts  only  cause  pulsations  when  greatly  diluted. 
Lactic  acid  stops  the  pulsations;"  alkaline  NaCl  solution  again 
restores  them.  Veratrine  and  digitalin  in  a  solution  of  NaCl 
also  cause  pulsations.1 

Schonlein  finds  that,  with  a  certain  strength  of  current  inter- 
rupted about  880  times  in  a  second,  the  muscles  of  the  water 
beetle  are  not  tetanised,  but  contract  rhythmically  from  two  to 
six  times  in  a  second.2 

Biedermann  has  succeeded  in  making  a  voluntary  muscle, 
such  as  the  sartorius,  contract  rhythmically  by  applying  a 
solution  of  sodium  bicarbonate  (2  per  cent.)  to  the  tibial  end, 
and  then  passing  a  constant  ascending  current  through  the 
muscle.3 

Pathology  of  Tremor. 

Bapid  alternation  of  contraction  and  relaxation,  or  tremor, 
may  be  observed  to  affect  either—  (a)  a  few  bundles  of  muscular 
fibres,  (6)  a  single  muscle,  or  (c)  groups  of  muscles. 

The  tremors  affecting  a  few  bundles  of  fibres,  or  fibrillary 
twitchings,  may  occur  in  excised  muscles,  and  are  probably  due 
to  some  conditions  of  the  muscular  fibre  allied  to  those  which 
have  already  been  considered  (p.  132).  They  may  occur  also  in 
muscles  which  still  remain  in  the  living  animal  after  the  nerve 
has  been  cut,  more  especially  in  the  muscles  of  the  tongue  after 
section  of  the  hypoglossal  nerve,  or  in  the  muscles  of  the  face 
after  section  of  the  facial  nerve.4 

Tremors  affecting  groups  of  muscles  occur,  in  some  cases, 
when  the  limbs  are  at  rest,  and  cease  during  voluntary  move- 
ment, as  in  paralysis  agitans ;  or  may  cease  entirely  when  the 
limb  is  at  rest,  and  only  come  on  when  the  muscles  are  put  in 

1  Sitzungsber.  d.  Wiener  Akad.,  Abth.  lxxxii.  p.  257-275. 
!  Schonlein,  du  Bois  Beymond's  Archiv,  1882,  p.  357. 
'  Sitzungsber.  d.  Wien.  Akad.,  Bd.  lxxxvii.,  Abt.  iii.,  March  1883. 
4  They  may  possibly  be  regarded  as  due  to  disturbance  of  the  normal  relations 
letween  longitudinal  and  transverse  contraction  in  muscular  substance. 


134  PHARMACOLOGY   AND   THERAPEUTICS,      [sect,  i.' 

action,  as  in  disseminated  sclerosis  and  in  mercurial  tremor. 
As  already  mentioned,  a  certain  number  of  motor  impulses  per 
second  are  required  to  keep  a  muscle  steadily  contracted. 

It  is  evident  that,  if  the  stimuli  proceeding  to  the  muscles 
from  the  nerve-centre  should  be  too  few,  tremor,  and  not  steady 
contraction,  of  the  muscle  will  occur.  And  the  same  will  be  the 
case  if  any  change  in  the  muscle  itself  should  render  the  duration 
of  each  single  contraction  less  than  usual. 

But  in  all  co-ordinated  movements  a  number  of  muscleB,  the 
actions  of  which  are  antagonistic  to  each  other,  are  brought  into 
play ;  and  it  is  by  the  proper  adjustment  of  these  antagonistic 
actions  that  the  performance  of  delicate  movements  becomes 
possible.  Unless  the  amount  of  contraction  of  each  of  these 
muscles  is  exactly  graduated,  there  will  be  a  tendency  to  oscilla- 
tory movement.  As  the  amount  of  contraction  in  each  muscle, 
or  group  of  muscles,  is  regulated  by  the  stimuli  sent  down  to 
it  from  the  nerve-centres,  it  is  evident  that  if  the  motor  cells 
supplying  one  group  of  muscles  be  affected  more  than  those 
which  supply  the  antagonistic  or  regulating  muscles,  inco-ordi- 
nation,  and  possibly  tremor,  will  occur.  The  pathology  of  tremor 
is  still,  however,  very  obscure. 

Treatment  of  Tremor. — If  tremor  should  depend  upon  in- 
sufficient rapidity  of  the  stimuli  passing  to  the  muscles  from  the 
nerve-centres,  it  is  evident  that  any  drug  which,  like  veratrine, 
will  increase  the  duration  of  each  individual  contraction,  is  likely 
to  be  of  use.  Acting  upon  this  idea,  Dr.  Ferris  has  used  vera- 
trine in  cases  of  tremor  due  to  alcoholism,  disseminated  sclerosis,  -' 
and  weakness  after  typhoid  fever.  Although  this  treatment  was 
successful  in  all  these  diseases,  it  does  not  seem  quite  certain 
that  the  utility  of  the  medicine  may  not  be  partially  due  to  its 
action  on  the  spinal  cord  as  well  as  on  the  muscles  themselves. 
In  one  case  of  tremor,  occurring  at  the  commencement  of  general 
paralysis,  I  have  given  salts  of  calcium  with  the  same  object  with 
the  apparent  result  of  arresting  the  tremor.  I  had  intended 
to  use  barium,  but  the  tremor  ceasing  for  many  months  with 
calcium,  I  have  not  proceeded  to  use  anything  else. 

Connection  between  Chemical  Constitution  and 
Physiological  Action  on  Muscle. 

I  have  already  mentioned  (p.  29)  that  one  can  hardly  look 
for  a  general  relation  between  the  atomic  weights  of  metals  and 
their  lethal  activity,  so  that  what  we  want  is  really  a  knowledge 
of  the  particular  relationship  of  each  group  of  elements  to  the 
organs  and  tissues  of  the  body. 

In  such  an  investigation  it  seems  natural  to  take  the  muscles 
first,  then  the  motor  nerves,  afterwards  the  nerve-centres  and 
individual  organs.    A  number  of  experiments  have  been  made  by 


chap.  v.J         ACTION   OF  DEUGS  ON  MUSCLE. 


135 


Cash  and  myself  in  order  to  do  this  for  the  alkalis  and  alkaline 
earths,  and  we  have  found  that  the  contractile  power  of  muscle, 
as  shown  hy  the  height  of  the  curve,  is  increased  by  rubidium, 
ammonium,  potassium,  and  caesium.  It  is  slightly  increased  or 
unaffected  by  sodium,  excepting  in  large  doses,  and  is  almost 
invariably  diminished  by  lithium. 

The  duration  of  contraction,  as  shown  by  the  length  of  the 
curve,  is  increased  by  rubidium  in  large  doses,  ammonium, 
sodium,  and  cesium.  It  is  shortened  by  ammonium,  lithium, 
rubidium  in  small  doses,  and  by  potassium. 

The  contracture,  or  viscosity,  is  increased  by  rubidium  in 
large  doses,  ammonium,  lithium,  and  sodium.  It  is  diminished 
by  rubidium  in  small  doses,  ammonium,  caesium,  and  potassium. 

Both  ammonium  and  rubidium  have  two  actions  on  muscle 
of  an  opposite  character,  sometimes  increasing  and  sometimes 
diminishing  both  the  duration  of  the  contraction  and  of  the  con- 
tracture, or  viscosity,  which  remains  after  the  ordinary  contraction 
has  ceased.  In  the  case  of  rubidium  this  appears  to  depend  upon 
the  dose,  but  we  were  not  satisfied  that  it  was  so  entirely  in  the 
case  of  ammonium  salts. 

In  regard  to  the  action  of  the  alkaline-earths  and  earths, 
we  found  that  the  contractile  power  "of  muscle  is  increased  by 
barium,  erbium,  and  lanthanum.  It  is  sometimes  increased  and 
sometimes  diminished  by  yttrium  and  calcium.  It  is  diminished 
by  didymium,  strontium,  and  beryllium. 

The  duration  of  contraction  is  increased  by  barium,  calcium, 
strontium,  yttrium,  and  erbium.  It  is  unaffected,  or  slightly 
diminished,  by  beryllium,  didymium,  and  lanthanum. 

Contracture  is  increased  by  barium,  calcium,  strontium, 
yttrium,  and  beryllium. 

The  contracture  produced  by  barium  is  enormous,  resembling 
that  produced  by  veratrine.  It  is,  like  that  of  veratrine,  dimin- 
ished by  heat,  cold,  and  potash,  and  may  be  abolished  by  these 


Increase  or  diminish 

afteraction  or  contracture. 

Increase.   0    Diminish. 


Increase  or 

diminish  altitude. 

Diminish.    0   Increase. 


Shorten  or 
lengthen  curve. 
Lengthen.   0   Shorten. 


Rb  (in  small  doses) 
Li  — 

Na(in  moderate  doses) . 

.  Sr  

Ca  

Rb  (large  doses)  ~— — 
Ba  — — 

NH4  (HC1)  — 


agents.  It  is  by  no  means  so  well  marked  when  the  drug 
is  injected  into  the  circulation  as  when  locally  applied  to  the 
muscle. 

The  action  of  some  of  the  more  important  of  those  drugs  can 


136  PHABMACOLOGY  AND  THERAPEUTICS,    ^sbct.i, 

be  graphically  represented  by  a  spiral,  the  terminal  members-of 
which  are  potassium  and  barium,  and  these  two  are,  to  a  certain 
extent,  connected  by  ammonium  as  an  intermediate  link. 

The  effect  of  one  member  of  one  of  these  groups  may  be 
diminished  or  increased  by  the  subsequent  application  of  another. 
Potassium  shortens  the  elongated  curves  caused  by  barium, 
calcium,  sodium  in  large  doses,  and  lithium,  and  reduces  the  con- 
tracture which  these  substances  cause.  The  veratrine-like  curve 
of  barium  is  counteracted  by  almost  all  the  substances  which 
produce  a  shorter  curve  than  itself. 

Action  of  Drugs  on  Muscle  is  Relative  and  not  Absolute. 

In  considering  the  action  of  drugs  on  muscle,  the  first  point 
which  comes  clearly  out  is  that  the  action  of  a  drug  on  the 
muscle  is  not  absolute,  but  merely  relative.  Thus  veratrine  and 
salts  of  barium  are  not  to  be  regarded  as  absolute  muscle- 
poisons — they  are  only  poisons  under  certain  conditions  of 
quantity  and  of  temperature.  An  exceedingly  small  dose  of 
veratrine,  instead  of  acting  as  a  poison  to  muscle,  acts  rather 
as  a  food,  and  restores  it  .when  exhausted.  Caffeine  likewise  in 
small  doses  has  a  restorative  action,  while  in  large  doses  it  is 
a  powerful  poison.  Veratrine  and  barium  in  moderate  doses 
and  at  moderate  temperatures  are  powerful  muscular  poisons, 
but  at  low  temperatures  and  at  high  temperatures  their  action 
is  to  a  great  extent,  or  even  completely,  abolished.  Nay  more, 
moderate  quantities  of  barium  salts  at  moderate  temperatures 
are  poisonous  to  the  normal  muscle,  but  they  are  restorative  to 
the  muscle  whose  composition  and  functions  have  been  already 
altered  by  rubidium.  Acids  and  alkalis  also  produce  an  effect 
on  muscle,  but  their  effect  depends  upon  whether  they  are  applied 
to  the  normal  muscle  or  to  one  previously  treated  with  a  substance 
having  an  opposite  reaction. 

It  is  evident,  then,  that  the  whole  question  of  the  action  of 
drugs  on  muscle  is  one  involving  the  relation  of  the  drug  to  the 
muscle  at  the  time  of  application,  and  we  must  expect  that  if  the 
temperature  is  different  from  the  normal,  or  if  the  composition 
of  the  muscle  should  vary,  the  action  of  the  drug  will  vary  like- 
wise. Now  the  composition  of  all  the  muscles  in  the  body  is  not 
the  same,  as  has  been  shown  by  Toldt  and  Nowak,1  and  the 
composition  of  the  ash  obtained  by  the  combustion  of  different 
animals  is  also  different,  as  has  been  shown  by  Lawes  and 
Gilbert.1  We  may  therefore  expect  that  muscular  poisons  will 
not  act  alike  at  the  normal  temperature  and  in  febrile  condi- 
tions, nor  alike  upon  all  the  muscles  of  an  animal ;  nor  will  they 

1  Quoted  by  Seegen,  Wien.  Akad.  Ber.  lxiii.  Abt.  ii.,  11-43. 
'  Proc.  Boy.  Soc,  xxxv.,  p.  344. 


chap,  v.]         ACTION  OP  DEUGS  ON  MUSCLE.      ,  137 

always  have  the  same  action  upon  different  animals— the 
relations  being  different,  the  effects  will  be  different.  The  effect 
of  poisons  upon  muscles  will  also  vary  according  to  the  chemical 
composition  of  the  tissue  at  the  time.  This  composition  may 
probably,  to  a  certain  extent,  be  altered  by  feeding— at  least  as 
far  as  regards  the  proportions  of  inorganic  ingredients.  We  know 
that  the  quantity  of  sodium  chloride  in  the  body  can  be  increased, 
for  if  an  animal  be  fed  with  a  larger  quantity  of  salt  than  usual, 
it  does  not  at  once  begin  to  excrete,  but  stores  it  up  for  two  or 
three  days,  and  then  the  excretion  increases.  After  the  ad-* 
ministration  of  the  salt  has  been  stopped  the  excretion  continues 
large  for  two  or  three  days,  and  then  returns  again  to  the  lower 
standard.  It  seemed  probable  that  similar  retention  would 
take  place  with  potash,  and  if  this  were  so,  we  might  expect  to 
counteract  to  a  great  extent  the  effect  of  barium  by  feeding  an 
animal  on  potash  for  some  time  before  administering  the  barium. 
On  trying  this,  Cash  and  I  have  found  that  this  is  the  case  to 
a  certain  extent,  and  although  we  have  not  been  able  com- 
pletely to  counteract  the  effect  of  a  large  dose  of  barium  so 
as  to  prevent  death  from  a  lethal  dose,  we  have  been  able  to 
modify  and  diminish  its  action  by  the  administration  of  potash 
for  several  days  previously,  so  that  the  characteristic  symptoms 
of  barium  poisoning  do  not  occur  until  some  hours  after  they 
would  otherwise  do  so,  and  thus  life  is  prolonged  though  not 
preserved. 

Action  of  Drugs  on  Involuntary  Muscular  Fibre. 

Contraction. — Involuntary  muscles,  with  the  exception  of 
the  heart,  differ  from  voluntary  not  only  in  their  anatomical 
structure  but  in  their  functional  activity :  instead  of  contracting 
or  relaxing  rapidly,  both  their  contraction  and  relaxation  are  slow. 
We  have  seen  that  although  voluntary  muscle  occasionally  ex- 
hibits spontaneous  rhythmical  contractions,  yet  these  occur  only 
under  exceptional  circumstances,  and  but  rarely.  Involuntary 
muscle,  on  the  other  hand,  has  a  much  greater  tendency,  to 
rhythmical  contraction,  although  it  may  be  regarded  as  doubtful 
whether  some  stimulus,  however  slight,  is  not  required  to  induce 
this  rhythm  even  in  involuntary  muscle.  It  has  been  already 
mentioned  that  the  contractile  tissue  of  medusa  will  beat  rhyth- 
mically so  long  as  it  is  connected  with  motor  ganglia.  When 
these  ganglia  are  removed,  the  contractions  cease,  but  will  again 
reappear,  notwithstanding  the  absence  of  the  ganglia,  if  a  con- 
stant stimulus  be  applied  to  the  contractile  tissue  itself.  This 
shows  that  the  conditions  for  rhythm  are  contained  in  contractile 
tissue  itself — that  the  rhythm  may  be  independent  of  the  ganglia 
with  which  the  contractile  tissue  is  connected  (p.  113).  The  same 
appears  to  be  the  case  with  involuntary  muscular  fibre  generally. 


138  PHAKMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

The  ventricle  of  the  frog's  heart,  containing  ganglia,  will 
beat  rhythmically  for  a  length  of  time  after  its  removal  from  the 
body.  If  the  ganglia  which  lie  close  to  the  auriculo- ventricular 
groove  be  cut  off,  the  rhythmical  action  will  cease  just  as  in  the 
medusa  when  the  marginal  ganglia  are  removed;  but  if  a  constant 
stimulus  be  applied  to  the  apex  of  the  heart,  as  for  example  by 
passing  a  constant  current  through  it,  or  by  distending  it  with 
serum,  its  rhythmical  movement  will  again  commence,  mechani- 
cal distension  appearing  to  have  upon  it  the  same  exciting  action 
that  a  little  acid  added  to  the  water  has  upon  the  nerveless  bell 
of  the  medusa. 

The  excitability  of  involuntary  muscular  fibre  appears  to  be 
increased  by  small  doses  of  atropine ;  for  when  the  ganglia  of 
the  frog's  heart  are  removed  the  apex,  instead  of  stopping  im- 
mediately, will  give  a  few  beats  before  it  stops  if  atropine  has 
been  previously  given,  and  mechanical  stimuli  cause  more  beats 
in  the  atropinised  than  in  the  normal  apex.1 

Effect  of  Stimuli. — Mechanical  distension  appears  to  be  one 
of  the  most  powerful  of  all  stimuli  to  excite  rhythmical  contraction 
in  involuntary  muscular  fibre. 

Luchsinger  observed  distinct  pulsation  in  the  veins  of  a  bat's 
wing  twenty  hours  after  the  death  of  the  animal,  if  artificial  cir- 
culation was  kept  up.  This  appears  to  show  that  the  power  of 
rhythmical  contraction  resides  in  the  muscular  fibres  of  the  veins, 
as  it  does  in  the  nerveless  apex  of  the  frog's  heart,  and  the  con- 
tractile tissue  of  the  medusa ;  but  here  also  an  external  stimulus 
appears  to  be  required  to  induce  contraction.  "When  the  pressure 
by  which  artificial  circulation  was  maintained  fell  to  zero,  the 
pulsation  stopped,  but  if  it  were  raised  to  forty  or  fifty  centi- 
metres of  water,  so  as  to  distend  the  vascular  wall,  rhythmical 
pulsation  again  commenced.  It  appears  possible,  however,  that 
when  involuntary  muscular  fibre  is  perfectly  healthy  and 
possesses  the  highest  degree  of  irritability,  it  may  contract 
rhythmically  without  any  extra  stimulus.  Thus  Engelmann2 
observed  that  the  ureter,  in  which  he  could  find  no  nerves  at  all, 
contracted  rhythmically  when  freshly  exposed,  although  it  was 
not  distended  or  subjected  to  any  mechanical  irritation ;  but  if 
artificial  respiration  has  been  long  kept  up,  and  the  animal  is 
exhausted,  so  that  the  excitability  of  the  ureter  is  diminished, 
then  the  effect  of  minimum  distension  in  increasing  its  rhythm 
becomes  very  evident. 

Cold  causes  the  isolated  non-striated  muscles  of  animals  to 
relax.     Heat  causes  them  to  contract.3 

The  influence  of  heat  and  cold,  however,  does  not  seem  to  be 
constant,  and  in  the  non-striated  muscle  of  frogs  they  have  an 

1  Langendorff,  Arehwf.  Anat.  u.  Phys.  Physiolog.,  Abtg.  1886,  p.  267. 

»  PflUger's  Archiv,  1869,  Bd.  11,  p.  251. 

'  Luchsinger  and  Sokolofl,  PflUger's  Archiv,  Bd.  26,  p.  465.      ■ 


eHAP.  v.]         ACTION  OF  DEUGS  ON  MUSCLE.  189 

opposite  connection  to  thai;  just  described.  It  is  probable  that 
the  different  results  may  depend  to  a  great  extent  upon  the 
amount  of  heat  or  cold  applied,  and  its  relation  to  the  condition 
of  the  tissues  at  the  time  of  application  ;  for  mechanical  stimu- 
lation has  also  an  opposite  effect,  according  to  its  amount ;  and 
while  gentle  stimulation  of  involuntary  muscular  fibre,  such  as 
that  of  the  small  blood-vessels,  causes  dilatation,  more  powerful 
irritation  produces  contraction.1 

The  influence  of  various  drugs  upon  involuntary  muscular 
fibre,  as  seen  in  the  contraction  of  the  blood-vessels,  will  be 
described  when  considering  the  circulation. 

The  Relation  of  the  Contractile  Tissue  to  the  Nerves 
is  different  in  voluntary  and  involuntary  muscular  fibre.  In  the 
latter  there  are  no  end  plates,  but  the  terminal  twigs  form 
a  plexus  around  the  fibres.  The  motor  nerves  of  involuntary 
muscular  fibre  appear  to  be  affected  by  atropine  and  its  con- 
geners in  a  similar  way  to  those  of  voluntary  muscle  by  curare. 
There  appears  also  to  be  a  certain  relationship  between  the  atro- 
pine and  curare  group.  Small  doses  of  atropine  paralyse  the 
motor  nerves  of  involuntary  muscle,  while  very  large  doses  of 
curare  are  required.  The  converse  is  the  case  with  voluntary 
muscle.  These  effects  are  usually  supposed  to  be  due  to  a 
definite  paralysing  action  on  the  nerves  themselves.  There  are 
difficulties,  however,  in  the  way  of  this  hypothesis,  and  a  more 
probable  one,  perhaps,  is  that  these  drugs  disturb  the  relations 
between  the  nerves  and  the  muscular  fibres  which  they  excite. 
On  the  idea  of  a  specific  action  it  seems  hard  to  explain  the 
results  obtained  by  Szpilman  and  Luchsinger,2  who  found  that 
atropine  produces  paralysis  of  the  motor  fibres  of  the  vagi  sup- 
plying the  oesophagus,  only  in  those  parts  of  it  where  involuntary 
muscular  fibre  is  present.  Thus  the  oesophagus  of  the  frog  and 
the  crop  of  birds  consist  of  involuntary  muscular  fibre,  and 
atropine  destroys  the  motor  power  of  the  vagus  over  them.  The 
oesophagus  of  the  dog  and  rabbit  contains  striated  muscular 
fibre,  and  atropine  does  not  paralyse  the  motor  nerves.  The 
oesophagus  of  the  cat  contains  striated  muscular  fibres  in  its 
upper  three-fourths,  and  non-striated  in  its  lower  fourth ;  atro- 
pine destroys  the  motor  action  of  the  vagus  upon  the  lower 
fourth,  but  not  upon  the  upper  part.3 

Propagation  of  Contraction  Waves. — Although  involuntary 
muscular  fibre  consists  of  short  cells  and  not  of  long  fibres  like 
voluntary  muscle,  yet  the  contraction  wave  may  be  propagated 
along  a  strip  of  involuntary  muscular  tissue  in  both  directions 
from  the  point  of  irritation,  just  as  in  voluntary  muscle  or  in 
the  contractile  tissue  of  medusae.     This  wave  is  transmitted 

1  Sigmund  Meyer,  Hermann's  Handb.  d.  Physiol.,  Bd.  5,  Theil  ii.,  p.  476. 
8  Szpilman  and  Luchainger,  PflUger's  ArcMv,  Bd.  26,  p.  459. 
•  Ibid.  p.  249. 


2 


140  PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  i.. 

more  slowly  in  involuntary  than  in  voluntary  muscle ;  and 
its  rate  in  the  involuntary  muscle  of  the  heart,  though  slower 
than  in  ordinary  striated  muscle,  is  quicker  than  iri  unstriated 
muscle,  so  that  in  this  respect  the  heart  is  intermediary  between 
the  two.1 

The  passage  of  contraction  waves  in  involuntary  muscular 
fibre  is  affected  by  the  same  conditions  as  voluntary  muscle, 
the  conduction  of  the  contractile  wave  being  rendered  slower  by 
fatigue  and  cold,  while  it  is  quickened  by  heat. 

Cold  and  fatigue  also  render  the  rhythmical  pulsations  smaller, 
and  longer,  while  heat  has  an  opposite  effect.  The  passage  of 
the  contraction  wave  may  also  be  diminished  or  arrested  by 
section  or  pressure,  just  as  in  the  contractile  tissue  of  medusae, 
so  that  instead  of  each  contraction  wave  passing  the  block  pro- 
duced by  the  sections  or  compression,  only  one  out  of  several, 
or  none  at  all,  may  pass.  The  proportion  passing  the  block 
depends  upon  its  completeness.  If  the  tissue  forming  the 
bridge  be  dry  as  well  as  narrow,  the  block  becomes  more  com- 
plete, and  may  be  again  diminished  by  moistening.  Variations 
in  the  strength  of  the  stimulus  do  not  affect  the  passage  of  the 
contraction  wave  over  the  block,  so  that  it  would  appear  that 
the  injury  caused  by  the  section,  along  with  the  narrowing  of  the 
conduction  path,  retards  the  re-establishment  of  the  conductive 
power. 

In  experiments  made  upon  the  heart  of  a  tortoise  cut  into  a 
strip,  it  has  been  found  by  Gaskell  that  stimulation  of  the  vagus 
removes  the  block,  quickens  the  recovery  of  the  tissue,  and  causes 
every  contraction  wave  to  pass.  The  effect  upon  the  muscle 
therefore  seems  to  be  trophic. 

A  weak  interrupted  current  applied  to  the  muscle  directly 
has  the  same  action  as  stimulation  of  the  vagus,  i.e.  it  increases 
the  conducting  power  of  the  muscle.  Sometimes,  however,  both 
the  vagus  and  a  weak  interrupted  current  have  an  opposite  effect, 
and  diminish  instead  of  increasing  the  conducting  power. 

An  artificial  rhythm  may  be  induced  in  a  strip  of  involuntary 
muscular  fibre  cut  from  the  heart  of  the  tortoise  by  passing  a  weak 
interrupted  current  through  it  and  then  stimulating  it  at  one  end 
by  induction  shocks,  at  intervals  of  about  five  seconds.  After  a 
while,  if  the  induction  shocks  are  discontinued,  the  muscle  still 
continues  to  contract  rhythmically  at  the  same  rate.  These  con- 
tractions, at  first  weak,  afterwards  become  strong,  and  may  last 
for  many  hours.  Both  the  conducting  and  the  contractile  power 
of  the  muscle  are  diminished  by  muscarine.  When  a  strip  of  it 
is  stimulated  by  induction-shocks  applied  to  one  end,  the  con- 
traction wave  passes  quickly  along ;  but  muscarine  appears  to 

1  Hermann's  Handbuch  d.  Physiologie,  Bd.  1,  p.  56. 

2  Engelmann,  Pflilger's  Archiv,  1875,  Bd.  11,  p.  465 ;   Gaskell,  Journal  of 
Physiology,  vol.  iii.  p.  367. 


chap.  v:j         ACTION  OF  DEUGS  ON  MUSCLE.  141 

block  its  transmission,  so  that  while  the  part  of  the  muscle 
between  the  electrodes  contracts  at  every  shock,  the  rest  of  the 
muscle  contracts  only  at  every  second  one.  A  weak  interrupted 
current  then  sent  through  the  muscle  may  lower  its  conducting 
power  and  still  further  reduce  the  force  of  the  contractions,  and 
not  only  block  the  passage  of  most  of  the  contraction  waves  from 
the  point  of  excitation,  but  may  even  prevent  the  contraction  of 
the  excited  part  itself. 

Atropine  has  an  opposite  action  and  appears  to  increase  the 
conducting  power  of  involuntary  muscle,  so  that  when  applied 
to  a  strip  of  the  heart,  the  conducting  power  of  which  has  been 
diminished  by  muscarine,,  the  contractility  is  at  once  increased^ 
and  each  contraction  wave  pass'es  over  the  whole  muscular  strip 
each  time  that  a  single  point  is  irritated.  Large  doses,  however,1 
appear  to  have  a  depressant  action  on  the  muscle. 

Hypothetical  Considerations  regarding  the  Action  of 
Drugs  on  Muscle. 

The  modifications  which  drugs  produce  in  the  functions  of  the  animal 
body  and  of  its  parts  are  so  numerous  and  varied  that  we  are  unable  fully 
to  explain  them  on  the  basis  of  our  present  physiological  knowledge.  The 
results  of  pharmacological  experiments  furnish  us  indeed  with  a  number  of 
additional  facts  regarding  the  functions  of  organs  and  tissues  which  will  ultl* 
mately  lead  us  to  a  more  correct  and  thorough  knowledge  of  their  physiology'. 
At  present,  however,  we  can  only  explain  them  hypothetically,  and,  indeed,  in 
many  cases  we  can  do  little  more  than  guess  at  the  explanation. 

The  advantage  to  be  gained  from  hypothetical  explanations  is  that 
hypotheses  not  only  lead  to  further  experiment,  but  serve  as  guides  for 
experiments,  by  which,  if  false,  they  may  be  soon  disproved,  or,  if  true,  may 
be  maintained. 

The  disadvantage  of  hypotheses  is  that  they  are  sometimes  apt  to  be 
taken  for  facts,  and  being  made  use  of  as  bases  for  further  speculation,  may 
lead  more  and  more  astray  from  the  truth.  While  bearing  in  mind  the 
danger  of  speculation,  it  may  be  useful  to  make  some  guesses  at  the  mode  of 
action  of  drugs  upon  the  muscle  as  guides  to  further  research. 

The  most  striking  point  about  muscle  is  the  motor  function  which  it 
exercises  by  contracting,  and  the  nature  of  its  contraction  must  engage  our 
attention.  Throughout  the  universe  we  find  that  motion  of  nearly  all  sorts 
resolves  itself  into  a  series  of  vibrations,  and  the  question  arises  whether  the 
motion  of  muscle  cannot  be  explained  in  the  same  way. 

When  a  muscle  is  stimulated  it.  contracts  and  relaxes  once,  describing  a 
wave-like  curve  upon  the  revolving  cylinder.  Frequently  this  first  wave  is 
followed  by  a  second,  and  sometimes  even  by  a  third,  which  are  usually 
ascribed  to  the  simple  elasticity  of  the  muscle.  Sometimes  we  can  notice 
that  the  single  contraction  wave  appears  really  to  consist  of  two  or  moie  par- 
tially superimposed  on  each  other,  and  sometimes  we  may  find  two  distinct 
waves  arise  from  one  stimulation. 

When  a  muscle  is  in  a  state  of  tetanic  contraction  it  appears  to  the  eye  to 
be  perfectly  quiet,  yet  we  know  that  during  this  period  of  apparent  rest  the 
muscle  is  in  a  state  of  vibration,  alternately  tending  to  contract  and  elongate. 
These  vibrations  may  succeed  one  another  with  a  rapidity  such  that  the 
muscle  appears  to  the  eye  to  be  motionless,  while  a  tracing  taken  upon  the 
revolving  cylinder  shows  distinct  successive  waves.  If  the  vibrations  are 
still  more  rapid,  the  waves  may  disappear,  and  we  get  the  muscle  describing 
a  straight  line.     But  even  when  a  muscle  is  entirely  relaxed,  its  parts  may 


142  PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

be  in  a  state  of  vibration  quite  as  continuous  as  in  tetanic  contraction.  This 
is  seen  by  examining  muscular  fibre  under  the  microscope.  The  phenomenon 
which  then  presents  itself  was  described  by  Porret  and  is  often  known  by  his 
name.  On  passing  a  constant  current  through  a  thin  muscular  slip  a  con- 
traction is  seen  when  the  current  is  closed.  During  the  whole  time  of  the 
passage  of  the  current,  the  muscle,  to  the  naked  eye,  appears  to  be  perfectly 
at  rest,  but  under  the  microscope  its  parts  are  seen  to  be  in  constant  motion, 
presenting  an  appearance  almost  exactly  similar  to  the  waving  of  a  field  of 
corn  on  a  windy  day,  or  to  the  motion  of  rows  of  cilia.  At  the  same  time  an 
actual  transference  of  material  takes  place  in  the  muscle :  the  end  next  the 
positive  pole  growing  smaller,  and  the  end  next  the  negative  pole  growing 
larger.  When  the  current  is  suddenly  reversed,  a  sudden  contraction  of  the 
whole  muscle  takes  place,  and  it  then  returns  to  apparent  rest ;  but  micro- 
scopic observation  shows  the  same  cilia-like  motion  as  before,  but  in  an 
opposite  direction. 

This  phenomenon  reminds  one  very  strongly  of  the  crowding  together  of 
carriages  in  a  railway  train  when  it  is  set  in  motion  or  stopped  by  the 
locomotive  pushing  behind  or  stopping  in  front.  Wo  know  that  the  apparent 
steady  movement  of  the  train  is  due  to  the  backward  and  forward  vibration 
of  the  piston  in  the  cylinders  of  the  locomotive,  and  the  question  occurs 
whether  the  contraction  of  the  muscle  as  a  whole  at  the  moment  of  opening 
and  breaking  the  current,  is  not  due  to  an  interference  with  the  rhythmical 
vibration  of  its  parts.  The  question  also  arises  whether  these  vibrations  are 
not  to  a  great  extent  dependent  upon  the  molecular  weight  of  its  constituents. 
This  seems  to  a  certain  extent  to  be  indicated  by  the  curious  relations  between 
the  effects  of  the  alkalis,  alkaline  earths,  and  certain  metals  upon  muscle. 
Thus  Cash  and  I  have  found  that  potassium  and  calcium  neutralise  the  action 
of  each  other  upon  muscle,  and  if  the  hypothesis  just  expressed  be  correct 
we  should  expect  that  metals  having  a  similar  molecular  weight  to  a  mixture 
of  calcium  and  potassium  would  have  no  action  upon  muscle.  This  appears 
to  be  the  case.  In  researches  made  in  Professor  Schmiedeberg's  laboratory, 
Anderson  Stewart  found  that  nickel  and  cobalt  had  no  action  upon  muscle, 
and  White  found  that  tin  also  had  little  or  none.  On  comparing  then  the 
atomic  weights  of  potassium  (39),  calcium  (40),  nickel  (59),  cobalt  (59),  and 
tin  (118),  we  get  the  following  relationships : 

K2  (78)  +  Ca  (40)  =  Ni2  (118),  or,  Co,  (118),  or,  Sn  (118.) 
Sodium  in  large  doses  lengthens  the  curve  and  increases  the  contracture 
when  applied  to  a  normal  muscle.  It  adds  to  the  length  of  the  long  curves 
caused  by  calcium  and  strontium.  Eubidium  in  large  doses  produces  a  long 
curve  with  enormous  contracture  almost  like  that  of  barium.  One  would 
naturally  have  expected  that  the  rubidium  and  barium  would  have  increased 
each  other's  effect  like  sodium,  calcium,  or  strontium ;  but  the  reverse  is  the 
case,  for  the  abnormal  curve  caused  by  rubidium  is  reduced  to  the  normal  by 
the  application  of  barium.  If  barium  be  applied  to  a  greater  extent  than  is 
sufficient  to  antagonise  rubidium,  it  first  abolishes  the  prolonged  rubidium 
curve,  reducing  it  to  the  normal,  and  then  again  elongates  it,  producing  its 
own  characteristic  curve.  Calcium  and  strontium,  which  also  prolong  the 
curve,  though  to  a  less  extent  than  barium,  do  not  antagonise  one  another's 
effect — they  rather  increase  it ;  but  calcium  reduces  the  barium  curve  to  the 
normal  before  causing  its  own  peculiar  curve.  At  first  sight  these  results 
seem  to  be  independent  of  any  rule,  but  a  curious  relation  is  to  be  observed 
between  the  atomic  weights  of  these  substances.  Thus  we  have  seen  that 
rubidium  in  large  doses  has  the  same  effect  as  barium  in  causing  a  veratrine- 
like  curve,  but  barium  destroys  the  effect  of  rubidium  before  producing  its 
own  effect.  On  comparing  the  atomic  weights  of  these  elements  we  find  that 
eight  atoms  of  rubidium  have  nearly  the  same  weight  as  five  of  barium,  and 
by  subtracting  one  from  the  other  we  get  almost  no  remainder.    Thus, 

Ba  137    x  5  =  685 

Eb  85-4  x  8  =  683'2 


chap,  v.]         ACTION  OF  DEUGS  ON  MUSCLE.  14y 

Potassium  is,  as  we  know,  an  important  constituent,  of  muscle,  and  it 
seems  possible  that  the  reduction  in  the  barium-curve  which  calcium  causes 
may  be  due  to  their  union  having  resulted  in  a  substance  whose  molecular 
weight  is  a  multiple  of  that  of  potassium.    Thus, 

Ba  137  x  2  =  274  -  Ca  40  =  234 
K     39  x  6=  234 

The  alterations  which  occur  in  voluntary  muscle  from  the  action  of  such 
substances  as  calcium  or  barium  appear  to  approximate  it  to  some  extent  to 
involuntary  muscle.  Voluntary  muscle  is  chiefly  characterised  by  sudden  and 
rapid  contraction  and  relaxation.  Involuntary  muscle  usually  contracts  and 
relaxes  slowly.  In  the  slowness  of  its  relaxation,  at  least,  the  muscle  poisoned 
by  barium  or  calcium  approaches  involuntary  muscle.  , 

The  power  of  summation  which  contractile  tissues  possess  is  strongly  sug- 
gestive of  the  idea  that  rhythmical  vibrations  of  gradually  increasing  intensity 
are  going  on  within  the  tissue  even  before  any  movement  becomes  visible.  A 
pendulum  very  gently  struck  at  proper  intervals  will  gradually  begin  to 
oscillate  through  a  larger  and  larger  arc.  If  touched  on  one  side  while 
oscillating,  the  effect  of  the  touch  will  depend  upon  the  time  at  which  the 
touch  is  applied,  for  at  one  period  of  oscillation  it  will  tend  to  impede,  and  at 
another  to  assist  the  oscillation.  Possibly  some  unseen  rhythm  in  the  muscle 
itself  may  be  the  cause  of  the  curious  variations  in  excitability  observed  in 
dying  muscles  and  in  muscles  poisoned  by  lead.  Two  pendulums  connected 
together  will  swing  harmoniously  if  their  rate  of  oscillation  is  the  same,  but 
if  one  be  loaded  so  as  to  alter  its  rate  of  oscillation  they  will  interfere  with 
each  other.  Possibly  the  effect  of  poisons  in  paralysing  nerves  may  be  due 
rather  to  alteration  in  the  relative  rhythms  of  the  nerve  and  muscle  than  to 
any  specific  destructive  power  on  the  terminations  of  the  nerve  itself. 

The  opposite  effects  which  Gaskell  has  noticed  the  vagus  nerve  and  a  weak 
induced  current  to  produce  upon  the  conducting  power  of  the  cardiac  muscle, 
sometimes  increasing  and  sometimes  diminishing  it,  may  be  due  to  the  inter- 
ference or  coincidence  of  rhythm  such  as  are  discussed  more  fully  farther  on 
under  the  head  of  Inhibition. 

It  is  impossible  to  say  at  present  what  the  true  cause  of  the  curious 
rhythmical  contractions  of  voluntary  muscle  is,  but  if  we  suppose  that  there 
is  a  transverse  as  well  as  a  longitudinal  contraction  in  muscle,  we  might 
regard  the  rhythmical  contractions  as  resulting  from  the  action  of  these  two 
opposing  forces. 

It  must  be  borne  in  mind  that  the  considerations  contained  in  this  section 
are  purely  hypothetical,  and  their  only  use  is  to  indicate  the  direction  in 
which  we  may  possibly  look  for  an  explanation  of  the  action  of  medicines  on 
muscle. 


IU  PHARMACOLOGY  AND  THERAPEUTICS.     Tsect.  u 


CHAPTEE   VI. 
'      ACTION  OF  DRUGS  ON  NERVES. 

General  Action  of  Drugs  on  the  Nervous  System. 

In  low  organisms  the  contractile  protoplasm  fulfils  the  func- 
tions of  both  nerve  and  muscle,  but  as  we  ascend  in  the  scale 
differentiation  becomes  more  and  more  complete.  From  their 
original  common  origin,  however,  we  might  expect  that  the 
poisons  which  act  on  the  muscles  would  also  act  on  the  motor 
nerves,  and  vice  versa,  and  we  should  hardly  expect  any  poison 
to  act  entirely  on  the  one  without  affecting  the  other.  This 
is  to  a  considerable  extent  the  case,  for  very  many  substances 
paralyse  them  both.  But,  as  one  would  also  expect  from  the- 
differentiation  they  have  undergone,  muscle  and  nerve  are  not 
equally  affected  in  the  higher  animals.  Thus  we  find  that 
although  most  of  the  salts  of  ammonium,  and  the  iodides, 
chlorides,  and  sulphates  of  the  compound  ammonias  into  which 
methyl  and  ethyl  enter,  paralyse  both  muscle  and  nerve,  yet 
they  paralyse  the:  nerve  before  the  muscle.  In  some  cases  the 
nerve  is,  affected  so  much  before  the  muscle  that  at  first  sight  it 
might  appear  that  the  nerve  alone  was  paralysed  and  the  muscle 
left  unaffected.  More  careful  observation,  however,  shows  us. 
that  most  of  the  compound  ammonias,  and  probably  most  of 
the  organic  alkaloids,  affect  muscle,  motor  nerves,  and  nerve-; 
centres,  and,  if  their  action  can  be  continued  long  enough,  will 
paralyse  all  three.  The  symptoms  they  produce  may,  however, 
be  entirely  different,  because  these  depend  upon  the  order  in 
which  the  different  parts  of  the  nervous  system  are  affected,  as 
has  already  been  pointed  out  at  p.  26.  The  symptoms  pro- 
duced, for  example,  by  strychnine  and  methyl-strychnine  ara 
utterly  different,  the  former  causing  tetanic  convulsions,  and 
the  latter  gradually-increasing  torpor,  weakness,  and  paralysis. 
Strychnine  stimulates  the  spinal  cord,  and  methyl-strychnine 
paralyses  the  motor  nerves ;  yet  if  their  action  continue  long 
enough  it  is  found  that  both  of  them  will  ultimately  cause 
paralysis  of  both  spinal  cord  and  motor  nerves.  The  final  result 
is  thus  the  same  in  both  cases,  but  the  order  in  which  the 
various  parts  of  the  nervous  system  are  affected  is  different. 


chap,  vi.]         ACTION  OF  DEUGS  ON  NERVES. 


145 


In  the  example  just  given,  the  drugs  appear  to  exert  a 
selective  influence  on  the  spinal  cord  and  motor  nerves  respect- 
ively, and  consequently  produce  very  different  symptoms.  But 
we  find  that  a  number  of  drugs  appear  to  act  upon  muscles, 
motor  nerves,  and  nerve-centres,  in  a  given  order,  although  there 
may  be  slight  variations  in  the  action  of  the  individual  drugs. 
These  substances  are  .generally  found  to  act  as  protoplasmic 
poisons,  arresting  the  movements  of  amoeba  and  white  blood- 
corpuscles,  as  well  as  proving  fatal  to  higher  animals. 

In  the  protoplasm  of  these  minute  organisms  we  are  unable 
at  present  to  distinguish  any  evidences  of  differentiation.  As  we 
ascend  in  the  animal  kingdom  we  find  a  differentiation  between 


Brain 


Medulla 


Respiratory  nerved 


Heart 


spinal  cord 


Centre  for 
sphincter* 


Sensory  and  motor  nerves 


Pig.  51. — Diagram  to  illustrate  Hughlings  Jackson's  views  of  the  nervous  sj'stem. 

muscle,  nerve,  and  nerve-centre ;  and  the  higher  up  we  ascend 
in  the  scale  the  more  complex  do  the  nerve-centres  become.  As 
Hughlings  Jackson  has  well  put  it,  '  evolution  is  a  passage  from 
the  most  simple  to  the  most  complex,  from  the  lowest  to  the 
highest  centres.'  It  is  a  passage  from  the  most  automatic  to  the 
most  voluntary ;  but  the  lowest  centres  are  at  the  same  time  the 
most  stable,  or,  as  Jackson  calls  it,  the  '  most  organised  centres ' ; 
while  the  highest  centres  are  the  most  unstable  or  least  organ- 
ised. This  is  represented  diagrammatically  in  Fig.  51,  where 
the  centres  for  the  heart  and  respiratory  apparatus  and  for  the 

L 


146  PHAKMACOLOGY  AND  THERAPEUTICS.  '  [sect,  u 

sphincters  are  represented  as  very  simple  in  their  organisation, 
but  very  stable,  as  indicated  by  the  size  of  the  ganglia  and  thick- 
ness of  the  nerves  in  the  diagram.  The  spinal  cord  is  represented 
as  more  complex,  but  with  thinner  lines,  in  order  to  show  its 
lesser  stability ;  while  the  high  complexity  and  small  stability  of 
the  cerebral  cortex  is  indicated  by  the  great  number  and  thin- 
ness of  the  lines  in  the  figure.  According  to  Jackson,  the  lowest 
nervous  centre  extends  from  the  aqueduct  of  Sylvius  to  the  lower 
end  of  the  spinal  cord ;  and  in  this  all  parts  of  the  body  are 
directly  represented,  so  that  a  discharge  of  nervous  energy  from 
any  part  of  it  only  requires  to  overcome  the  resistance  in  the 
motor  nerves .  and  the  muscles,  themselves.  What  he  regards 
as  the  middle  motor  centres  are  evolved  out  of  the  lowest,  and 
re-represent  all  parts  of  the  body  in  more  complex  and  special 
combinations.  The  highest  centres  evolved  out  of  the  middle 
re-re-represent  all  parts  of  the  body  in  still  more  complex  and 
special  combinations.  A  discharge  from  the  highest  centres,  in 
order  to  act  on  the  periphery,  has  to  overcome  the  resistance  of 
the  middle,  and  lowest  centres,  as  well  as  of  the  muscles. 

In  the  action  of  such  poisons  as  alcohol,  the  nervous  system 
appears  to  be  paralysed  in  inverse  order  of  its  development :  the 
highest  centres  going  first,  next  the  middle,  and  then  the  lowest. 
After  this  comes  paralysis  of  the  motor  nerves,  and  lastly  of  the 
muscles  themselves.  In  the  ease  of  alcohol,  the  dose  required  to 
paralyse  motor  nerves  and  muscles  is  so  great  that,  as  a  rule,  we 
can  only  observe  its  effect  by  directly  applying  the  drug  to  the 
nerves  and  muscles  themselves.  To  such  a  process  of  paralysis 
as  this,  Jackson  applies  the  term  of  dissolution. 

In  the  case  of  drugs  which  excite  nervous  centres,  we  also 
notice  a  certain  similarity  of  action.  Thus  strychnine  not  only 
causes  convulsions  by  its  stimulating  action  on  the  medulla 
spinalis,  but  stimulates  also  the  nerve-centres  for  the  respiration 
and  circulation  in  the  medulla  oblongata  and  in  the  heart  itself. 

Action  of  Drugs  on  Motor  Nerves. 

The  readiness  with  which  a  muscle  responds  to  a  stimulus 
depends  both  on  the  condition  of  the  muscle  itself,  and  on  the 
terminations  of  motor  nerves  within  it.  A  faradaic  current 
readily  stimulates  the  nerve-endings,  but  does  not  act  at  all 
readily  on  the  muscle.  The  making  and  breaking  of  a  constant 
current,  on  the  other  hand,  has  comparatively  slight  action  on 
the  nerves,  but  a  powerful  action  on  the  muscle.  One  of  the 
questions  which  arises  most  constantly  in  connection  with  the 
action  of  drugs  is :— whether  or  not  they  paralyse  the  end  of 
the  motor  nerves  in  muscle.  This  question  was  fully  worked 
out  by  -Bernard,  and  also  independently  by  Kolliker,  in  relation 
to  curare. 


chap,  vi.]         ACTION  OF  DEUGS  ON  NEEVES.  147 

The  same  methods  of  experiment  were  adopted  by  both. 
They  were  twofold,  and  consisted : 

1.  In  applying  the  poison  to  that  part  of  the  body  alone  which 
seemed  affected  by  it,  and  seeing  whether  it  produced  its  usual 
action. 

2.  In  preventing  it  from  reaching  that  part,  and  seeing 
whether  its  usual  effect  was  then  absent. 

The  first  of  these  methods  consisted  in  the  local  application 
of  the  drug  to  the  muscles  and  motor  nerves  themselves  (Pigs.  52 
and  53).  The  second  consisted  in  ligaturing  the  artery  of  one 
leg  in  a  frog,  so  as  to  prevent  the  poison  from  reaching  the 
muscles  and  motor  nerves  in  that  leg  (Pig.  54) . 

The  advantage  of  the  first  method,  viz.  that  of  local  appli- 
cation, is  that  it  allows  us  to  deal  with  only  one  organ  at  a 
time,  and  the  results  are  therefore  less  complicated  than  those 
of  the  second  method.  In  some  respects  it  is  better  to  begin  with 
the  second  method  and  work  back  to  the  simpler  from  the  more 
complex  organs  (p.  149). 

Paralysis  of  Motor  Nerve  -  endings. —  Curare  produces 
symptoms  of  paralysis.  Paralysis  may  be  due  to  the  action 
of  the  drug  on  the  muscles  themselves,  on  the  motor  nerves 
which  set  them  in  action,  or  on  the  nerve-centres  which  originate 
motor  impulses.  In  order  to  decide  this,  Bernard  applied  elec- 
tricity to  the  nerves  and  to  the  muscles  of  a  frog  poisoned  by 
curare  administered  subcutaneously.  He  thus  found  that  when 
the  nerve  was  irritated  no  effect  was  produced  on  the  muscles ; 
but  that  when  the  muscle  itself  was  stimulated,  it  contracted 
readily.  In  order  to  decide  whether  this  loss  of  irritability  in 
the  nerve  was  due  to  a  change  in  the  nerve-trunk,  or  in  the  ter- 
minations within  the  muscle,  Bernard  employed  the  first  method, 
that  of  local  application.  He  placed  a  solution  of  curare  in  two 
watch-glasses.    In  one  he  immersed  the  trunk  of  the  nerve  (Fig. 


Fig.  52. — Shows  the  method  of  applying  a  drug  in  solution  locally  to  the  trunk  of  a  nerve. 

52),  and  in  the  other  the  muscle,  so  that  the  solution  penetrating 
between  the  fibres  could  reach  the  nerve-endings  (Fig.  53).    He 


FiQ.  53.— Shows  the  method  of  applying  a  drug  in  solution  locally  to  a  muscle  and  the  ends 
of  motor  nerves  within  it. 

then  irritated  the  nerve  attached  to  both  muscles,  and  found 
that  irritation  caused  contraction   readily  enough  in  the  case, 

l2 


148 


PHARMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


Where  the  nerve-trunk  had  been  steeped  in  the  solution  of  curare, 
but  had  no  effect  when  the  curare  had  been  allowed  to  reach  the 
nerve-ends  by  immersion  of  the  muscle  in  the  solution.  The 
irritability  of  the  muscle  itself  to  mechanical  stimuli,  or  to  the 
making  and  breaking  of  a  constant  current  directly  applied  to 
it,  remained  quite  unaltered,  so  that  the  muscular  fibre  had 
evidently  not  been  affected  by  the  action  of  the  poison. 

The  second  mode  of  testing  the  action  of  drugs  upon  motor 
nerves,  viz.  that  of  local  protection,  consists,  as  has  been  stated, 
in  allowing  the  drug  to  be  carried  to  the  muscles  and  nerve-endings 


3FIG.'  54.— Diagram  of  the  mode  of  experimenting  on  motor  and  sensory  nerves  in  the  frog. — The 
shaded  part  shows  where  the  poison  has  been  carried  by  the  cumulation.  The  unshaded  left  leg 
shows  where  the  tissues  have  been  protected  from  the  poison  by  ligature  of  the  artery  just 
above  the  knee.  The  unbroken  lines  with  arrows  pointing  to  the  spinal  cord  indicate  the 
sensory  nerves.  The  broken  line  with  arrows  pointing  outwards  indicates  the  motor  nerve  to 
the  unpoisoned  leg. 

by  the  circulating  blood  in  one  leg  of  a  frog,  while  it  is  prevented 
from  reaching  the  other  either  by  ligaturing  (Fig.  54)  the  blood- 
vessels alone,  or  ligaturing  tbe  whole  leg  with  the  exception  of  the 
sciatic  nerve.  After  some  time  has  elapsed,  the  sciatic  nerve  is 
stimulated  on  eacb  side.  If  the  muscles  of  the  poisoned  limb  do 
not  contract  at  all  or  do  so  more  feebly  than  in  the  unpoisoned 
limb,  it  is  evident  that  the  poison  has  paralysed  either  them  or 
the  motor  nerves.  In  order  to  .decide  whether  the  nerves  or  the 
muscles  are  paralysed  the  muscle  is  next  stimulated  directly ;  if 
it  then  contracts  normally  it  is  evident  that  the  paralysis  ob- 
served when  the  nerve  was  irritated  is  due  to  the  action  of  the 


chap,  vi.]         ACTION  OF  DRUGS  ON  NERVES.  149 

drug  on  the  nerve-endings.  If  the  muscle  is,  completely  para- 
lysed, no  definite  conclusion  can  be  drawn  regarding  the  nerve- 
endings,  but  if  the  muscle  shows  only  partial  paralysis,  and  the 
paralysis  is  greater  when  the  nerve  is  stimulated  than  when  the 
muscle  is  stimulated  directly,  we  conclude  that  the  drug  has 
acted  upon  both  the  muscular  substance  itself  and  the  motor 
nerve-endings  within  it. 

The  effect  of  drugs  in  paralysing  motor  nerves  is  chiefly  in- 
vestigated in  frogs  as  the  action  comes  out  much  more  distinctly 
in  them. 

Warm-blooded  animals  may  die  from  paralysis  of  the  motor 
nerves  while  the  nerves  still  respond  readily  to  faradaic  stimuli 
.applied  to  them,  the  faradaic  stimulus  being  much  greater  than 
that  normally  sent  along  the  nerves  from  the  nerve-centres. 
Thus  after  an  animal  has  been  killed  by  paralysing  it  with 
curare,  its  muscles  will  still  respond  readily  to  electrical  stimu- 
lation of  the  motor  nerves. 

A  fallacy  to  be  guarded  against  in  experiments  on  the  results 
of  preventing  a  poison  from  reaching  one  part  of  the  body  is 
that  caused  by  diffusion.  Even  when  the  circulation  is  stopped 
in  a  frog's  leg  by  ligature  of  the  artery,  poison  introduced  into 
the  dorsal  lymph-sac  may  pass  down  the  limb  by  diffusion  and 
affect  the  parts  below  the  ligature.  This  may  be  to  a  great 
extent  prevented  by  ligaturing  the  whole  limb  en  masse,  at  the 
same  time  carefully  excluding  the  sciatic  nerve  from  the  ligature. 
Diffusion  may  also  occur  although  the  circulation  has  been  stopped 
throughout  the  whole  body  by  removal  of  the  heart  and  other 
viscera,  and  the  anterior  part  of  the  spinal  cord  may  be  affected 
before  the  posterior  when  the  poison  is.  injected  into  the  dorsal 
lymph-sac. 

Advantage  of  the  Method  of  Local  Protection.:— The 
advantage  of  this  method  is  that  it  affords  information  regarding 
the  action  of  the  poison  upon  other  parts  of  the  nervous  system,. 
viz.  the  nerve-centres  and  sensory  nerves,  as  well  as  upon.  the 
motor  nerves.  It  also  gives  the  order  in  which  the  poison  affects 
the  various  nervous  structures,  and  shows  whether  the  quantity 
of  poison  conveyed  to  the  nerves  by  the  circulation  is  sufficient 
to  paralyse  them  or  not.  For  some  substances,  directly  applied 
to  the  ends  of  the  motor  nerves,  may  paralyse  them,  although 
they  do  not  have  this  effect  when  injected  into  the  blood : 
the  reason  being  that  the  quantity  applied  to  the  nerves  directly 
may  be  much  greater  than  that  which  reaches  them  through  the 
circulation. 

The  muscles  and  ends  of  the  motor  nerves  being  protected 
in  the  ligatured  leg  from  the  action  of  the  poison,  while  it  still 
remains  in  connection  with  the  nerve-eentres  by  means  of  the 
sciatic  nerve,  this  method  serves  as  an  index  to  show  what  is 
going  on  in  the  nerve-centres..     Thus  in  a  frog  poisoned  by 


150 


PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


curare  it  is  found  that  the  ligatured  leg  moves  on  irritation 
of  the  sensory  nerves,  while  all  the  poisoned  parts  remain  per- 
fectly still.  This  shows  that  the  afferent  nerves  are  still  capable 
of  conveying  impressions  to  the  spinal  cord,  and  the  cord  itself 
of  reflex  action,  although  the  poisoned  limbs  give  no  indication 
of  the  changes  which  are  occurring  in  the  nerve-centres.  By- 
and-by  irritation  of  a  sensory  nerve  or  root  ceases  to  produce 
any  movement  even  in  the  ligatured  limb.  This  effect  is  shown 
to  be  due  to  paralysis  of  the  nerve-centres  by  observing  the 
effect  of  irritation  of  the  nerves  in  the  ligatured  limb,  for  the 
muscles  still  respond  readily  to  irritation  of  .the  nerve  by  a 
moderate  stimulus.  We  may  conclude  with  tolerable  certainty 
that  the  motions  have  ceased  in  the  limbs  because  the  nerve- 
centres  have  become  paralysed. 

Paralysers  of  Motor  Nerves.— Many  other  drugs  have 
an  action  somewhat  similar  to  that  of  curare  upon  the  motor 
nerves : — 


ammonium 
ammonium 
ammonium 


Ammonium  cyanide.1 

„  iodide. 

Ethyl  ammonium  chloride.1 
Amyl  ammonium  chloride.1 

„  „  iodide.1 

Amyl  ammonium  sulphate.1 
Phenyl  -  di  -  methyl  -  ethyl 

iodide.13 
Phenyl  -  di  -  methyl  -  amyl 

iodide.13 
Phenyl  -  di  -  methyl  -  amyl 

hydrate.13 
Phenyl-tri-ethyl  ammonium  iodide.13 
Tri-methyl  ammonium  iodide.2 
Tri-ethyl  „  chloride, 

iodide. 
„  „  sulphate. 

Methyl-tri-ethyl  stibonium  iodide.14 
Methyl-tri-ethyl         „         hydrate.14 
Toluyl-tri-ethyl  ammonium  iodide.13 
Di-toluyl-di-ethyl        „  „    13 

Toluyl-di-ethyl-amyl  „ 
Toluyl-tri-ethyl  „ 

Tetra-methyl  „ 

Tetra-ethyl  „ 

Tetra-methyl  „ 

Tetra-amyl  „  „     " 

Tetra-ethyl  phosphonium  iodide.1* 
Tetra-ethyl  arsonium  iodide.1' 
Tetra-ethyl  arsonium  and  zinc  double 

iodide.14 


hydrate.13 
iodide. 

r      » 

iodide.13 


and    cadmium 


Tetra-ethyl    arsonium 
double  iodide." 

Anchusa. s 

Methyl  anilin.4 

Ethyl        „      4 

Amyl         „      4 

Methyl-atropine.2 

Methyl-brucine.2 

Ethyl-brucine.3 

Camphor. 

Methyl-cinchonine.* 

Amyl  „         » 

Chloroxethylene. 

Methyl-codeine.2 

Collidine. 

Conime. 

Di-methyl-coniine.! 

Cotarnine.3 

Cynaglossine.5 

Di-methyl  ammonium  chloride.' 
iodide.1 
sulphate.1 


Di-ethyl 


Curarine." 

Curare.' 

Dita'ine.8 

Methyl-delphinine.' 

Echium.3 

Erythrina  corallodendron.* 


chloride.1 

iodide.1 

sulphate.1 


1  Brunton  and  Cash,  Proc.  Boy.  Soc. 

2  Crum-Brown  and  Fraser,  Trans,  of  Roy.  Soc.  of  Edinburgh. 
8  Buchheim  and  Loos,  Eckhard's  Beitrage,  Bd.  v. 

4  Jolyet  and  Cahours,  Compt.  Bend.,  lxvi.  p.  1181. 

*  Diediilin,  Med.  Centralbl.,  1868,  p.  211. 

i  Preyer,  QBttmger  Ztschr.  f.  Chemie,  1,  p.  381. 

'  Bernard  and  Kolliker. 

'  Hamack,  Arch.f.  exp.  Path.  u.Pharm.,  vii.  p.  126. 


chap,  vi.]         ACTION  OF  DEUGS  ON  NERVES.  151 


Guachamacha.10 
Lobeline. 

Methyl-morphine.2 
Methyl-nicotine.2 
Ethyl  „       ' 

Ptomaines." 
Methyl-quinine.3 
„      quinidine.2 


Methyl-piperidine. 
Saponine. 
Sparteine. 

Methyl-strychnine.2,  12 
Ethyl  „         2 

Methyl-thebaine.2 
Methyl-veratrine.' 
Amyl  „      3 


Although  the  substances  mentioned  in  the  above  list  have  all 
the  power  of  paralysing  motor  nerves,  they  do  not  possess  the 
same  power  as  curare.  In  the  case  of  the  salts  of  ammonium 
and  the  compound  ammonias,  the  curare-like  action  is  accom- 
panied by  a  paralysing  effect  upon  the  muscular  substance  and 
on  the  nerve-centres.  When  salts  of  these  substances  are  em- 
ployed, their  effect  is  somewhat  modified  by  their  acid  radical, 
although  this  is  not  the  case  to  the  same  extent  in  the  salts  of 
the  compound  ammonias,  and  in  the  salts  of  ammonium  itself. 
Thus  the  iodide  of  ammonium  has  a  much  stronger  paralysing 
action  on  the  nerves  than  bromide,  chloride,  sulphate,  or  phos- 
phate, and  this  is  observed  also,  though  to  a  less  extent,  in  the 
salts  of  the  compound  ammonias.1 

Exact  Localisation  of  the  Action  of  Curare. 

The  experiments  already  described  have  shown  that  curare 
does  not  paralyse  the  trunks  of  motor  nerves  (p.  148),  nor  the 
muscular  substance  (p.  148),  and  does  paralyse  the  peripheral 
terminations  of  the  motor  nerves  within  the  muscles :  but  they 
do  not  show  what  the  exact  part  of  the  peripheral  terminations  is 
on  which  the  drug  exerts  its  action. 

When  a  nerve  enters  a  muscle  it  divides  and  subdivides 
dichotomously  until  the  fibres  become  single,  and,  losing  their 
myelin  sheath,  the  axis-cylinders  enter  the  muscular  fibres. 
There  they  end  in  the  nerve-plates,  from  which  the  ultimate 
branches  pass  to  the  muscular  substance. 

The  paralysis  produced  by  curare  may  be  due  to  its 
action  on : 

(a)  The  single  nerve-fibrillae  before  they  completely  lose  their 
myelin  sheath ; 

(b)  The  axis-cylinders ; 

(c)  The  end  plates ; 

(d)  The  ultimate  branches. 

As  curare  acts  so  much  more  readily  on  the  nerves  passing 

•  Harnack,  Buchheim's  Pharmacologic,  3rd  ed.  p.  615. 

10  Sachs,  Archivf.  Physiol.,  1877,  p.  91 :  Schiffer,  Deutsch.  med.  .Wochenschr., 
1882,  No.  28. 

"Several  authors  quoted  by  Guareschi  and  Mosso,  Les  Ptomaines,  1883. 

12  Schroff,  Wochenblatt  d.  Ztschr.  d.  Aertze  zu  Wien,  No.  14,  1866. 

"  Kabuteau,  TraiU  ilimentaire  de  Thirapeutique,  4me  ed.  p.  530  et  seq. 

lt  Vulpian;  Arch.de Physiologie,  1868.  i    --    : -  ...  . 


152  PHABMACOLOGY  AND  THEEAPEUTICS.     Isect.  i. 

to  voluntary  than  on  those  passing  to  involuntary  muscles,  and 
the  most  marked  anatomical  difference  between  these  two  kinds  of 


Tig.  55".— Curve  stowing  tlie  excitability  in  different  pirts  of  the  sartorial  of  a  frog  in  a  normal  and 

curarised  muscle, 

muscles  consists  in  the  termination  of  the  former  in  end  plates, 
it  is  natural  to   suppose  that  curare  acts  upoa  these  plates. 


Pig.  56.— Shows  the  distribution  of  the  nerves  in  the  gastrocnemius  of  the  froff  and  the  curve  of 
excitabi.ity  in  different  parts  of  the  muscle.  It  will  be  observed  that  the  excitability  is  greatest 
in  those  parts  where  there  ane  most  nerve-endings. 

Moreover,  this  supposition  appears  to  receive  confirmation  from 
the  observation  of  Kiihne — that  the  end  plates  undergo  a  certain 
alteration  in  poisoning  by  curare,  their  outlines  becoming  more 


chap,  vi.]         ACTION  OF  DRUGS  ON  NERVES.  158 

distinct  than  in  the  normal  condition.  This  slightly  increased 
sharpness  of  outline  may  be  regarded  as  indicating  a  slight 
physical  change,  which  might,  however,  be  associated  with  such 
profound  chemical  changes  in  the  end  plates  as  to  destroy  their 
power  of  conducting  stimuli  from  the  nerve  to  the  muscle. 

But  recent  researches  by  Kiihne  and  one  of  his  pupils, 
Politzer,  appear  to  render  it  probable  that  some  of  the  nerve- 
structures  within  the  muscle  retain  their  functional  activity  even 
in  profound  poisoning  by  curare ;  and  Politzer  supposes  that  the 
part  of  the  nerve  which  is  acted  on  by  curare  is  the  nerve-fibril 
before  it  has  quite  lost  its  medullary  sheath,  and  that  the  poison 
destroys  the  conducting  power  of  the  nerve  by  acting  on  the 
cement-substance  at  Ranvier's  nodes.  The  grounds  on  which 
this  supposition  is  based  are  that,  even  in  profound  poisoning  by 
curare,  those  parts  of  the  sartorius  of  the  frog  which  contain 
nerve-endings  are  more  irritable  than  those  which  contain  none 
(Fig.  56),  and  that  the  irritability  increases  or  diminishes  in 
proportion  to  the  number  of  nerve-endings,  just  as  it  does  in 
the  normal  muscle,  although  the  excitability  of  all  the  parts 
containing  nerves  is  less  than  normal  in  curare-poisoning. 

That  this  variation  in  irritability  in  different  parts  of  the 
muscle  is  due  to  nervous  structures,  and  not  to  variations  in  the 
muscular  fibres  themselves,  is  shown  by  the  fact  that,  when  the 
excitability  of  the  nerve  is  depressed  by  throwing  it  into  a  state  of 
anelectrotonus,  these  variations  in  the  excitability  of  the  muscle 
disappear. 

It  is  just  possible  that  the  nervous  structures  which  retain 
a  certain  amount  of  excitability  in  curare-poisoning  may  be  the 
ultimate  terminations  which  pass  from  the  motor  plate  to  the 
muscular  fibre :  but  Politzer  appears  to  throw  this  possibility 
aside,  and  considers  that  the  amount  of  nervous  excitability  re- 
tained shows  that  all  the  parts  beyond  the  last  node  of  Ranvier 
still  possess  their  functions. 

Should  Politzer' s  supposition — that  curare  paralyses  motor 
nerves  by  acting  on  the  cement  at  Ranvier's  nodes — be  correct, 
it  may  perhaps  serve  to  explain,  not  only  the  difference  between 
jts  action  on  motor  nerves  going  to  voluntary  and  those  going  to 
involuntary  muscular  fibre,  but  also  the  difference  between  the 
action  of  curare,  or  poisons  having  a  similar  action,  and  of 
atropine  on  the  inhibitory  fibres  of  the  vagus. 

Action  of  Drugs  in  Increasing  Excitability  of  Motor  Nerves. 

It  is  not  so  easy  to  prove  positively  that  a  drug  has  increased 
'as  that  it  has  diminished  the  excitability  of  motor  nerves.  The 
fact  that  the  nerves  of  the  poisoned  leg  are  found  to  be  more 
excitable  than  those  of  the  ligatured  one  in  such  experiments  as 
those  just  described,  does  not  prove  it,  for  it  must  be  borne  in 


154  PHAEMACOLOGY  AND  THEEAPEUTICS.     LSect.  r. 

mind  that  the  arrest  of  the  circulation  in  the  ligatured  leg 
lessens  the  excitability  of  the  muscles  and  the  nerves  in  it. 
This  effect  of  the  ligature  strengthens  the  proof  that  a  drug  has 
produced  paralysis  when  we  find  that,  in  spite  of  the  freer  circu- 
lation, the  poisoned  leg  is  less  irritable  than  the  ligatured  one ; 
but  it  prevents  our  concluding  that  the  drug  has  increased  ex- 
citability when  we  find  that  the  poisoned  leg  responds  more 
readily  to  stimuli  than  the  ligatured  one. 

To  try  whether  a  drug  increases  excitability  we  treat  two 
muscles  with  saline  solution,  and  after  ascertaining  that  their 
excitability  is  alike  we  add  the  drug  to  be  tested  to  the  saline 
solution  in  which  one  muscle  is  steeped,  and  after  some  time  test 
the  excitability  again.  If  the  muscle  in  the  poisoned  saline  solu- 
tion becomes  more  excitable  than  the  other,  we  conclude  that  the 
increase  is  due  to  the  action  of  the  drug. 

Irritation  of  Motor  Nerve-endings  by  Drugs. — The  peri- 
pheral terminations  of  motor  nerves  in  muscle  appear  to  be 
irritated  by  certain  poisons,  so  that  the  excised  muscle  exhibits 
fibrillary  twitchings.  This  might  be  due  to  irritation  of  the 
muscular  structure  itself,  but  as  they  are  gradually  abolished 
by  curare  they  are  supposed  to  depend  upon  irritation  of  the 
terminations  of  motor  nerves.  The  poisons  which  produce  this 
effect  are :  aconitine,  camphor,  guanadine,  nicotine,  pilocarpine, 
pyridine.  Physostigmine  produces  it  most  markedly  in  warm- 
blooded animals,  but  does  not  seem  to  cause  it  in  frogs. 

Action  of  Drugs  on  the  Trunks  of  Motor  Nerves. — Nerve- 
trunks  are,  as  a  rule,  very  much  less  affected  by  poisons  than  the 
end-plates ;  but  they  may,  nevertheless,  be  also  acted  upon  by 
strong  solutions  of  a  poison.  It  appears  necessary  to  apply  the 
poison  locally  to  them,  and  they  are  probably  little  if  at  all 
affected  by  poisons  introduced  into  the  system  generally.  The 
action  of  poisons  is  tested  by  placing  a  small  piece  of  gutta- 
percha tissue  under  the  nerve-trunk,  usually  the  sciatic  of  the 
frog,  and  applying  the  poison  directly  to  it,  or  dipping  the  nerve 
into  a  weak  solution  of  common  salt,  or  of  sodium  phosphate,  to 
which  the  poison  has  been  added,  and  comparing  the  poisoned 
nerve  with  one  dipped  into  a  similar  saline  solution  without  the 
poison. 

There  are  two  methods  of  comparison.  The  first  consists 
in  using  the  contraction  of  the  corresponding  muscle  as  an 
index  of  the  functional  power  of  the  nerve;  the  second  in 
ascertaining  the  effect  of  the  poison  on  the  normal  electrical 
current  in  the  nerve. 

The  motor  fibres  of  a  nerve  appear  to  have  their  excitability 
abolished  more  readily  than  that  of  sensory  nerves  by  changes 
in  the  body  generally,  and  sometimes  also  by  the  local  application 
of  drugs  to  them.  Thus  in  wounded  nerves  the  motor  function 
may  be  destroyed,  while. the  sensory  function  is  little  alteredj 


ttup.  vi.]         ACTION  OF  DEUGS  ON  NEEVES.  155 

and  where  both  sensibility  and  motion  have  been  destroyed  by 
a  bruise  of  the  nerve-trunk,  tbe  sensibility  may  reappear,  while 
the  motor  power  does  not.  In  rheumatic  neuralgia  there  is  not 
unfrequently  motor  paralysis  with  exaggerated  sensibility.  When 
a  solution  of  physostigmine  is  applied  locally  to  the  nerve-trunk 
for  a  while,  and  the  nerve  is  then  irritated  beyond  the  point  of 
application,  it  is  found  tbat  it  will  produce  reflex  movements  of 
the  body  after  it  has  ceased  to  do  so  in  the  limb  supplied  by  the 
nerve,  which  shows  that  the  sensory  fibres  can  still  conduct  im- 
pressions, though  the  motor  fibres  cannot.  Longer  application 
of  the  poison  will  destroy  the  sensory  fibres  also.  When  a  paste 
of  theine  is  applied  to  the  sciatic  nerve,  or  the  nerve  is  dipped 
in  a  solution  of  opium,  similar  results  are  observed. 

By  dipping  nerves  in  a  solution  of  the  poison  Mommsen  finds 
that  atropine  diminishes  the  irritability  of  the  nerves,  affecting 
first  the  intramuscular  endings,  and  afterwards  the  trunks. 
Alcohol,  ether,  and  chloroform  first  increase  and  then  diminish 
the  irritability. 

Action  of  Drugs  on  Sensory  Nerves. 

The  general  action  of  a  drug  on  sensory  nerves  is  much 
more  difficult  to  ascertain  with  precision  than  its  effect  upon 
motor  nerves,  because  the  evidences  of  sensation  we  have  in  the 
lower  animals  are  cries,  and  movements  either  of  the  limbs  or 
involuntary  muscles,  such  as  the  iris,  arteries,  or  bladder,  which 
ensue  on  irritation  of  sensory  nerves. 

In  the  production  of  these  movements  or  cries,  many  struc- 
tures are  concerned,  viz.  sensory  nerves,  nerve-centres,  spinal  or 
cerebral  motor  nerves,  and  muscles.  It  is  comparatively  easy 
to  ascertain  the  local  action  of  the  drug  upon  sensory  nerves,  for 
in  this  case  these  other  structures  are  not  affected.  By  applying 
the  substance  to  one  part  of  the  body,  either  by  painting  it  upon, 
or  injecting  it  under,  the  skin,  and  then  comparing  the  effect  of 
stimulation  produced  by  pinching  or  by  the  application  of  heat 
or  electricity  upon  that  and  other  parts  of  the  surface,  we  can 
see  whether  or  not  the  sensibility  of  the  sensory  nerves  has  been 
affected  by  the  drug. 

But  when  the  drug  is  absorbed  into  the  circulation,  it  may 
affect  all  the  other  structures  already  mentioned,  as  well  as  the 
sensory  nerves,  and  thus  it  may  be  impossible  to  decide  with 
certainty  whether  these  nerves  are  affected  or  not.  But  even 
here  definite  results  are  sometimes  obtainable,  as  in  the  case  of 
curare.  The  method  of  experimenting  is  that  of  local  protection, 
arresting  the  circulation  in  one  leg  of  a  frog  by  applying  a  ligature 
to  the  sciatic  artery.  The  animal  is  then  poisoned  with  curare, 
or  any  drug  the  action  of  which  is  to  be  ascertained.  The 
poison  is  carried  by  the  circulation  to  all  other  parts  of  the  body 
excepting  the  ligatured  leg. 


156  PHAEMACOLOGY  AND  THEBAPEUTICS.     [sect.  i. 

In  the  case  of  curare  the  motor  nerves  are  paralysed  by  the 
drug,  and  it  would  be  impossible  to  ascertain  whether  irritation 
of  the  sensory  nerve  produced  any  effect  at  all,  were  it  not  that 
the  ligatured  limb,  retaining  its  irritability,  serves  as  an  index 
to  the  condition  of  the  nerve-centres.  At  first  it  is  found  that 
pinching  the  poisoned  foot  will  cause  movements  in  the  non- 
poisoned  leg.  This  shows  that  the  sensory  nerves  retain  their 
irritability  and  transmit,  the  stimulation  up  to  the  spinal 
cord,  whence  it  is  reflected  down  the  motor  nerves  to  the  non- 
poisoned  foot. 

As  the  poisoning  becomes  deeper,  however,  pinching  the 
poisoned  leg  produces  much  less  effect. 

This  might  be  due  to  paralysis  of  the  spinal  cord,  but  it  is 
shown  that  this  is  not  the  case  by  pinching  the  ligatured  leg  just 
above  and  below  the  ligature. 

It  is  found  that  a  pinch  just  below  the  ligature  causes  marked 
reaction,  while  a  pinch  just  above  has  little  or  no  effect. 

In  this  experiment  all  the  structures  concerned  in  the  move- 
ment have  been  alike  subjected  to  the  action  of  curare  with  the 
exception  of  the  ends  of  the  sensory  nerves  below  the  ligature. 
It  is  thus  evident  that  the  diminished  reaction  from  pinching 
above  the  ligature  is  due  to  paralysis  of  the  ends  of  the  sensory 
nerve,  in  the  part  of  the  body  to  which  the  poison  has  had  access, 
and  which  is  shaded  dark  in  the  engraving  (Pig.  54). 

In  the  experiment  just  mentioned,  the  second  of  the  two 
methods  already  described  (p.  147)  in  the  reference  to  motor  nerves 
is  employed,  and  the  action  of  the  drug  on  the  ends  of  sensory 
nerves  is  ascertained  by  preventing  the  poison  from  reaching 
them;  but  the  first  method  may  also  be  employed  and  the 
action  ascertained  by  applying  the  poison  to-  the  ends  of  the 
sensory  nerves,  while  the  nerve-trunks  and  nerve-centres  are 
protected  from  its  action.  Thus,  in  the  experiments  of  Liegeois 
and  Hottot  upon  the  action  of  aconitine  on  the  sensory  nerves, 
they  ligatured  the  vein  and  injected  the  poison  into  the  artery  of 
a  frog's  leg;  the  poison  was  thus  carried  to  the  ends  of  the 
sensory  nerves  in  the  skin,  while  it  was  prevented  from  reaching 
the  nerve-centres.  In  this  way  they  found  that  irritation  of  the 
poisoned  skin  ceased  to  produce  any  reflex  action,  while  stimula- 
tion of  the  trunk  of  the  nerve  distributed  to  that  leg  still  caused 
well-marked  reflex  action.  Normally  the  terminations  of  a  sensory 
nerve  in  the  skin  are  much  more  sensitive  than  the  trunk  of 
the  nerve;  and  this  experiment  therefore  proves  that -aconitine 
paralyses  the  ends  of  the  sensory  nerves. 

The  local  action  of  drugs  on  the  sensory  nerves  in  man  is 
ascertained  by  producing,  when  applied  locally,  either  diminution 
in  pain  which  may  be  present  at  the  time,  or  insensibility,,  which 
is  usually  ascertained  by  the  sesthesiometer.  This  instrument 
is  simply  a  pair  of  compasses  with  blunt  points  and  a  scale 


chap,  vi.]         ACTION  OP  DEUGS  ON  NEEVES.  157 

by  which  the  distance  of  the  points  from  one  another  can  be 
read  off. 

"When  the  sensation  is  acute,  the  points  are  distinctly  felt  as 
two,  even  when  they  are  but  slightly  separated  from  one  another  ; 
but  when  the  sensation  is  blunt,  they  are  felt  as  one  when  they 
are  at  a  considerable  distance  apart. 

In  frogs  the  local  action  on  sensation  is  ascertained  by  dipping 
one  leg  for  some  time  in  the  solution  to  be  tested,  and  then 
comparing  the  effect  of  irritating  corresponding  points  in  the  two 
feet  or  legs  by  pinching,  by  the  application  of  acids,  or  by  a  faradaic 
current.  In  this  way  it  has  been  ascertained  that  hydrocyanic 
acid  has  a  powerful  local  action  in  paralysing  sensory  nerves. 
Where  the  drug  is  very  powerful,  its  action  on  the  nerve-centres 
might  complicate  the  result,  if  a  sufficient  quantity  should  be 
absorbed  into  the  blood.  This  fallacy  may  be  avoided  by  arresting 
the  circulation  entirely  through  excision  or  ligature  of  the  heart. 

Local  Sedatives  and  Local  Anaesthetics. — Local  sedatives 
are  substances  which  diminish,  and  local  anaesthetics  are 
substances  which  destroy,  the  sensibility  of  the  skin  for  the  time 
being. 

Local  Sedatives.  Local  Anaesthetics. 

Aconite.  Extreme  cold. 

Atropine.  Ice. 

Belladonna.  Ether  spray. 

Carbolic  acid.  Carbolic  acid. 

Chloroform.  Cocaine. 

Chloral.  Kawa-resin.1 
Morphine. 
Opium. 
Veratrine. 

Action. — Their  effect  in  some  degree  is  due  to  a  paralysing 
action  upon  the  terminal  branches  of  the  cutaneous  nerves.  It 
is  probably,  to  some  extent,  also  due  to  an  effect  upon  the  vessels 
and  tissues  analogous  to  that  which  is  produced  by  rubbing  or 
scratching,  which,  as  everyone  knows,  gives  temporary  relief  to 
itching.  Sweating  also  relieves  the  itching,  which  is  sometimes 
felt  just  before  it  begins. 

Uses. — Local  sedatives  are  employed  to  relieve  itching  and  to 
lessen  pain,  whether  it  be  due  to  neuralgia  or  inflammation.  Local 
anaesthetics  are  employed  temporarily  to  abolish  the  sensibility 
of  the  skin,  and  allow  slight  incisions  or  operations  to  be  made 
painlessly. 

Stimulating  Action  of  Drugs  on  the  Peripheral  Ends 
of  Sensory  Nerves. —  The  peripheral  terminations  of  sensory 
nerves  appear  to  become  more  sensitive  when  the  supply  of  blood 

1  Lewin,  Ueber  Piper  methysiicum  (Kawa).    Berlin,  1886. 


158  PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

to  the  part  is  increased.  This  is  markedly  seen,  not  only  in 
inflammation,  where  the  part  becomes  exceedingly  tender,  but  in 
cases  where  turgescence  of  the  vessels  occurs  under  physiological 
conditions.  Besides  the  class  of  irritants  which  act  on  the  peri- 
pheral terminations  of  sensory  nerves  so  as  to  cause  pain  when 
locally  applied,  there  are  several  drugs  which  appear  to  have  a 
special  irritant  action  on  the  ends  of  sensory  nerves  when  intro- 
duced into  the  circulation :  these  are  aconite  and  aconitine,  which 
give  rise  to  a  peculiar  tingling  and  numbness  in  the  tongue,  lips, 
cheeks,  and  indeed  in  all  parts  supplied  by  the  fifth  nerve.  Vera- 
trine  also  causes  peculiar  sensations  in  the  sensory  nerves  when 
taken  internally,  but  these  are  felt  more  in  the  fingers  and  toes, 
and  in  the  joints,  than  in  the  tongue.1 

1  Von  Schroff,  Pharmacologic,  4th  ed.  p.  584. 


CHAPTEE  VII. 
ACTION  OP  DRUGS  ON  THE  SPINAL  COED. 

In  the  spinal  cord  we  have  to  distinguish  three  functions  :  that 
of  conduction,  that  of  reflex  action,  and  that  of  origination  of 
nerve-force!  as  in  the  sweat-centres,  &c,  contained  in  it. 

The  spinal  cord  transmits  sensory  or  afferent  impulses 
upwards  to  the  medulla  and  brain ;  and  motor  impulses  down- 
wards to  the  muscles,  as  well  as  other  efferent  impulses  to  the 
glands.  It  transmits  reflex  impulses  across,  either  from  behind 
forwards,  or  laterally  from  one  half  of  the  cord  to  the  other. 
Transmission  from  behind  forwards  occurs  when  the  impulse 
passes  from  the  sensory  to  the  motor  columns  on  the  same  side, 
as  in  the  case  of  reaction  of  a  sensory  stimulus  on  the  same  side 
of  the  body.  It  occurs  laterally  when  the  sensory  stimulus  pro- 
duces motion,  not  on  the  same  side,  but  on  the  opposite  side  of 
the  body. 

Action  on  the  Conducting  Power  of  the  Cord. — Its  con- 
ducting power  for  motor  impulses  is  assumed  to  be  impaired 
when  it  is  noticed  that  any  drug  causes  partial  paralysis  of  the 
hinder  extremities  of  an  animal  before  the  anterior  extremities. 

It  is  usually  tested  by  irritating  the  spinal  cord  at  its  upper  end,  either 
mechanically  with  the  point  of  a  needle,  or  by  a  galvanic  or  faradaic  current 
passed  through  electrodes  inserted  into  it  close  together,  and  observing 
whether  irritation  of  the  cord  itself  in  this  way  causes  contraction  in  the 
muscles  of  the  legs. 

When  no  contraction  is  produced  by  irritation  of  the  cord 
itself,  while  direct  irritation  of  the  motor  nerves  can  still  produce 
vigorous  contraction,  it  is  evident  that  the  cause  of  the  paralysis 
must  be  that  the  spinal  cord  has  lost  its  power  to  conduct  motor 
impulses. 

These  experiments  may  be  made  in  a  frog,  the  cerebrum  of  which  has 
been  previously  destroyed;  and  they  may  be  confirmed  in  warm-blooded 
animals  where  sensibility  has  been  destroyed  by  a  section  of  the  cord,  just 
below  the  medulla,  and  respiration  is  kept  up  artificially.  The  spinal  cord  is 
then  exposed,  and  the  anterior  columns  are  irritated  in  the  ways  already 
mentioned. 

The  power  of  the  cord  to  conduct  sensory  impressions  is 
ascertained  by  exposing  it  under  anaesthetics  and  allowing  their 
influence  to  pass  so  far  off  that  the  animal  is  capable  of  giving 


160  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  r. 

evidence  of  sensation.  The  posterior  roots  are  then  irritated 
before  and  after  the  injection  of  the  poison  into  the  circulation. 

When  it  is  found  that  after  the  poison  is  injected  the  irrita- 
tion of  the  posterior  roots  which  previously  caused  evidence  of 
sensation  no  longer  produces  any  effect,  while  irritation  of  the 
anterior  columns  still  produces  motion,  the  conclusion  appears  to 
be  just,  that  the  poison  has  paralysed  the  conducting  power  of 
the  sensory  columns  of  the  cord. 

This  action  appears  to  be  possessed  by  caffeine,  for  Bennett 
found  that  while  irritation  of  the  posterior  roots  of  the  cord 
caused  violent  struggles  and  loud  cries  in  a  rabbit  before  the  in- 
jection of  caffeine  into  the  circulation,  similar  irritation,  after  the 
injection,  caused  only  a  slight  quiver.  That  this  effect  was  not 
due  to  motor  paralysis  was  shown  by  the  fact  that  irritation  of 
the  anterior  columns  caused  violent  muscular  contractions  after, 
the  injection  as  well  as  before  it.' 


FIBRE  IN 
LATERAL 
COLUMNS 


SENSORY 
ROOT 


Fig.  57.— Diagram  to  show  the  effect  of  chloroform,  chloral,  and  other  anaesthetics  on  conduction  of 
painful  impressions  in  the  spinal  cord. 

Ordinary  impressions  of  touch,  temperature,  and  muscular 
action  are  transmitted  through  the  posterior  roots  of  the  spinal 
cord  to  the  ganglia  of  the  posterior  horn  of  the  grey  substance, 
and  thence  upwards  by  the  fibres  of  the  lateral  columns.  Painful 
sensations,  however,  appear  to  be  transmitted  upwards  through 
the  grey  substance  of  the  cord.  The  afferent  nerves,  which  trans- 
mit impressions  from  one  part  of  the  cord  to  another,  so  as  to 
produce  co-ordinated  reflex  movement,  are  contained  in  the 
posterior  columns  of  the  cord. 

It  is  evident  that  any  injury  or  poison  which  chiefly  affects 
the  grey  matter  so  as  to  diminish  its  conducting  power  may 
abolish  pain  while  reflex  action  still  persists.  This  condition  may 
be  produced  by  division  of  the  grey  matter  of  the  cord,  and  it 
occurs  also  at  a  certain  stage  of  the  action  of  anaesthetics  such  as 
chloroform  and  ether. 

The  action  of  drugs  on  the  power  of  the  spinal  cord  to  con- 
duct reflex  stimuli  both  transversely  and  longitudinally  has 
been  carefully  investigated  by  Wundt.     He  first  ascertains  the 

1  Hughes-Bennett,  Edin.  Med.  j'ourn.,  Oct.  1873. 


chap,  vn.]  ACTION  OF  DEUGS  ON  THE  SPINAL  COED.    1G1 

time  which  elapses  between  the  application  of  a  stimulus  to  a 
motor  nerve  and  the  contraction  of  a  muscle,  the  nerve  used 
being  the  sciatic,  and  the  muscle  the  gastrocnemius  of  a  frog. 
This  time,  which  includes  that  requisite  for  the  stimulus  to 
travel  down  the  motor  nerve  and  to  set  the  muscle  in  action,  he 
terms  the  direct  latency.  He  next  stimulates  a  sensory  root  of 
the  spinal  nerve  at  the  same  level  and  on  the  same  side  as  the 
motor  nerve,  taking  care  that  the  stimulus  does  not  act  on  the 
motor  nerve  directly,  but  only  reflexly  through  the  cord.  The  time 
between  the  application  of  the  stimulus  and  the  commencement 
of  contraction  he  terms  the  total  latency.  By  deducting  the 
direct  latency  from  the  total  latency,  he  ascertains  the  time  re- 
quired for  the  stimulus  to  pass  through  the  grey  matter  of  the 
cord  from  the  posterior  to  the  anterior  horn  of  the  same  side. 
This  he  calls  the  reflex  time. 

The  time  required  for  transverse  conduction  is  ascertained 
by  applying  the  stimulus  to  a  posterior  root  on  the  other  side  and 
comparing  the  latency  with  that  of  stimulation  to  a  posterior  root 
on  the  same  side. 

The  time  required  for  longitudinal  conduction  is  ascertained 
by  applying  a  stimulus  to  the  brachial  nerve,  so  that  it  has  to 
travel  down  the  greater  part  of  the  length  of  the  spinal  cord 
before  it  can  excite  the  sciatic  nerve.    By  comparing  the  latent 


POSTERIOR 
ROOT       o 


\V/A  SECTION  Of 
;  „  n    SPINAL 
U^Uy      CORD 


I    )  MUSCLE 


Pig.  58.— Diagram  to  show  the  method  of  investigatinjrreflexand  transverse  conduction  In  the  spinal 
cord.  The  motor  nerve  is  first  irritated.it  1.  As  the  cylinder  revolves  at  a  known  rate,  ai  d  a 
mark  is  made  upon  it  by  an  electro-magnet  at  the  instant  the  nerve  is  irritated,  the  distance 
between  this  mark  and  the  commencement  of  the  muscle  curve  indicates  the  time  required  for 
the  irritation  to  travel  down  the  motor  nerve  to  the  muscle  and  set  it  in  action.  The  irritation 
is  next  applied  to  the  posterior  root  on  the  same  side  (  2 ).  The  distance  between  the  commence- 
ment of  contraction  in  this  case  and  in  that  where  the  motor  nerve  was  irritated  gives  the  time 
required  for  simple  reflex  transmission  of  the  stimulus  from  the  posterior  to  the  anterior  horn 
of  the  cord.  The  stimulus  is  then  applied  1  o  the  posterior  root  on  the  opposite  side  at  3,  and 
the  distance  between  the  commencement  of  the  consequent  contraction  and  that  of  the  curve 
obtained  by  irritating  at  2  gives  the  time  required  for  transmission  across  the  cord. 

period  of  excitation  in  the  brachial  nerve  with  that  of  the  sciatic 
on  the  same  side l  the  length  of  time  required  for  longitudinal 

1  For  convenience  sake  both  the  sciatic  and  the  brachial  nerves  are  taken  in 
this  experiment  on  the  opposite  side  from  the  muscle,  so  that  the  time  of  longi- 

M 


1C2  PHARMACOLOGY  AND  THERAPEUTICS,     [sect,  t, 

transmission  of  stimuli  in  the  cord  is  ascertained.  The  mode  of 
ascertaining  the  time  of  ordinary  reflex  and  transverse  trans- 
mission in  the  cord  is  shown  diagrammatically  in  Fig.  58. 

The  differences  in  the  latent  period  and  in  the  form  of  the 
muscle  curve  obtained  by  irritation  of  the  motor  nerve,  and  by 
simple  transverse,  and  longitudinal  reflex  stimulation,  are  shown 
diagrammatically  in  Fig.  59.     Wundt  found  that  when  a  motor 


Win  59  — Diagram  to  show  tlie  difference  between  the  length  of  the  latent  period  and  form  ot  the 
carve  in  contraction  induced,  B,  by  direct  irritation  of  the  motor  nerve ;  o,  by  simple  reflex  from 
irritation  of  the  cord  on  the  same  side  ;  and  D,  by  cross  reflex  from  irritation  of  the  cord  on  the 
oonosite  side  to  that  from  which  the  motor  nerve  proceeds,  as  shown  in  Pig, ,58  i  shows  com- 
bined transverse  and  longitudinal  reflex ;  A  indicates  the  moment  at  which  the  stimulus  was 
applied  in  each  case. 

nerve  was  irritated  at  a  point  distant  from  the  muscle  the  xe- 
sulting  contraction  had  not  only  a  longer  latent  period,  but  was 
less  in  height  and  longer  in  duration  than  when  the  nerve  was 
irritated  close  to  the  muscle.  From  a  comparison  of  the  curves 
it  will  be  seen  that  a  small  portion  of  grey  matter  has  a  similar 
effect  upon  the  stimulus  which  passes  through  it  that  a  great 
length  of  nerve-fibre  would  have.  In  all  reflex  actions,  there- 
fore, in  the  normal  animal,  the  contraction  of  the  muscle  has  a 
longer  latent  period,  less  height,  and  longer  duration  than  that 
produced  by  direct  irritation  of  the  motor  nerve.  The  increase 
in  the  latent  period,  diminution  in  height,  and  longer  duration 
are  greater  in  the  case  of  transverse  than  of  simple  reflex,  and 
greater  still  in  the  case  of  combined  transverse  and  longitudinal 
reflex. 

In  the  normal  frog  a  stronger  stimulus  is  necessary  to  pro- 
duce reflex  contraction  than  would  be  sufficient  if  it  were  applied 
directly  to  the  motor  nerve,  and  strong  and  weak  stimuli  will 
produce  strong  and  weak  muscular  contractions.  The  spinal  cord 
has  a  power  of  summation  similar  to  that  already  referred  to  in 
the  case  of  contractile  tissue  of  medusae,  so  that  a  stimulus  which 
would  be  powerless  to  produce  a  reflex  contraction  if  applied 
once  to  a  posterior  root  or  to  a  sensory  nerve  will  be  effectual  if 
repeated  several  times  in  close  succession. 

Strychnine  has  an  effect  on  the  conducting  power  of  the 
spinal  cord  which  we  should  hardly  expect,  and  so  have  other 
convulsant  poisons.  It  increases  the  excitability  so  much  that 
slighter  stimuli  than  before  will  produce  reflex  action,  and  it 
destroys  to  a  considerable  extent  the  power  of  summation,  so 
that  instead  of  each  stimulus  producing  a  contraction  in  propor- 

tudinal  conduction  is  ascertained  by  deducting  the  transverse  from  the  combined 
transverse  and  longitudinal  conduction. 


chap,  vii.]  ACTION  OF  DEUGS  ON  THE  SPINAL  COED.    1G8 

tion  to  its  strength,  all  have  the  same  effect — a  weak  one,  which 
is  just  strong  enough  to  produce  an  effect  at  all  causing  as  great 
a  contraction  as  the  most  powerful.  The  time  required  for  the 
transmission  of  stimuli  through  the  cord  is  enormously  increased, 
so  that  the  latent  period  of  ordinary  reflex,  and  still  more  of 
transverse  and  longitudinal  reflexes,  is  greatly  increased,  some- 
times, indeed,  to  as  much  as  ten  times  the  normal.  The  retarda- 
tion of  transverse  conduction  is  not  absolutely  greater  than  of 
longitudinal  conduction  ;  but,  as  the  distance  through  which  the 
stimulus  has  to  pass  in  the  former  case  is  much  less  than  in 
the  latter,  it  follows  that  strychnine  increases  the  resistance  more 
transversely  than  longitudinally.  Morphine  in  small  doses  has 
no  very  marked  action  upon  the  cord,  but  larger  doses  have  an 
action  almost  exactly  like  that  of  strychnine,  causing  increased 
reflex  irritability,  tetanic  contractions,  and  prolonged  latency. 
Veratrine  has  a  similar  action.  Nicotine  and  coniine  in  small 
doses  have  a  similar  action  to  strychnine,  but  this  is  quickly 
masked  by  the  rapid  appearance  of  paralysis.  When  large  doses 
are  used,  paralysis  occurs  almost  immediately,  and  is  usually 
accompanied  by  fibrillary  twitchings.  Atropine  has  at  first  an 
action  similar  to  strychnine  in  causing  increased  excitability, 
prolonged  latency,  and  tetanic  contraction.  It  differs  from 
strychnine  in  causing  more  rapid  diminution  in  the  irritability 
of  the  grey  substance  of  the  spinal  cord  and  in  diminishing  the 
conducting  power  of  peripheral  nerves.  In  consequence  of  this, 
irritation  of  the  sciatic  nerve  in  a  frog  poisoned  by  atropine 
causes  two  contractions,  one  direct  and  one  reflex,  separated  from 
each  other  by  a  distinct  interval,  whereas,  in  a  frog  poisoned  by 
strychnine,  these  two  contractions  begin  almost  at  the  same 
moment  and  appear  superimposed  upon  each  other.1 

Effect  of  Drugs  on  the  Reflex  Action  of  the  Cord. — The 
effect  of  drugs  upon  the  reflex  action  of  the  spinal  cord  is  usually 
estimated  by  the  time  which  elapses  between  the  application  of 
a  stimulus  and  the  occurrence  of  reflex  action,  before  and  after 
the  administration  of  a  drug.  Longer  time  indicates  diminished, 
and  shorter  time  increased,  excitability  of  the  cord. 

Method  of  Experimenting:. —  Since  the  spinal  cord  in  mammals  quickly 
loses  its  excitability  when  deprived  of  oxygenated  blood  (as  shown  by 
Stenson's  experiment,  p.  164),  frogs  are  used  for  experiment.  The  method 
usually  employed  is  called  Tiirck's  method.  The  cerebral  lobes  in  a  frog  are 
destroyed,  and  after  sufficient  time  has  elapsed  ib  allow  it  to  recover  from 
the  shock,  it  is  suspended  either  by  the  head  Or  fore -legs,  so  that  the  hind- 
legs  hang  down.  A  very  dilute  solution  of  sulphuric  acid,  the  acid  taste  of 
which  can  be  little  more  than  perceived  by  the  tongue,  is  put  in  a  small 
beaker  and  raised  until  one  foot  of  the  frog  is  completely  immersed  in  it. 

1  According  to  W.  Stirling,  the  latent  period  of  reflex  action  in  the  spinal  cord 
is  increased  by  the  chloride  and  bromide  of  potassium  and  ammonium,  by  lithium 
salts,  and  by  chloral  and  butyl-chloral ;  it-  is  decreased  by  the  chloride,  bromide, 
and  iodide  of  sodium. — Stirling  and  London'  Physiology,  2nd  ed.,  vol;  ii.  p.  909. 


164  PHAEMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

The  time  is  then  counted  by  means  of  a  metronome,  between  the  immersion 
of  the  foot  in  the  acid  solution  and  the  time  when  the  leg  is  drawn  up  out  of 
it.  As  soon  as  the  foot  is  drawn  up,  the  acid  is  carefully  washed  off  with 
some  fresh  water  in  order  to  prevent  any  injury  to  the  skin,  and  after  a 
minute  or  two,  the  experiment  may  be  repeated.  When  the  time  seems 
constant  the  drug  is  injected  into  the  lymph-sac,  and  the  experiment  is 
repeated  again.  The  greater  or  less  time  which  is  required  for  the  withdrawal 
of  the  foot  from  the  acid  after  the  injection  of  the  poison,  as  compared  with 
the  time  required  before,  shows  the  extent  to  which  the  reflex  action  of  the 
spinal  cord  has  been  diminished  or  increased  by  the  poison. 

Direct,  Indirect,  and  Inhibitory  Paralysis  of  the  Spinal 
Cord  by  Drugs. — When  it  is  found  that  the  reflex  action  of 
the  cord  is  greatly  diminished  or  apparently  entirely  abolished, 
it  must  not  be  at  once  concluded  that  this  is  necessarily  due  to 
the  direct  paralysing  action  of  the  drug  itself  upon  the  nervous 
substance  of  the  cord.  This  may  be  the  case,  and  is  so  when 
methyl-coniine  is  employed,  but  it  may  be  due  to  the  indirect 
action  of  the  drug  upon  the  heart,  weakening  the  circulation,  and 
lessening  the  function  of  the  cord  by  interfering  with  its  blood- 
supply. 

In  order  to  ascertain  whether  this  is  the  case  or  not,  it  is  usual  to  take  two 
frogs  as  nearly  alike  as  possible,  to  destroy  the  brain  in  each,  and  after 
waiting  until  they  have  recovered  from  the  immediate  shock  of  the  operation, 
to  inject  into  one  the  drug  to  be  tested,  and,  at  the  moment  when  it  stops  the 
beating  of  the  heart,  to  tie  a  ligature  around  the  heart  of  the  other.  The 
persistence  of  reflex  action  is  then  tested  in  the  usual  manner,  and  if  it  is 
found  that  it  disappears  much  sooner  in  the  poisoned  frog  than  in  the  other  one 
in  which  the  heart  has  been  ligatured,  it  is  concluded  the  drug  has  paralysed 
the  substance  of  the  cord  itself. 

Indirect  Paralysis. — The  spinal  cord  is  very  rapidly  para- 
lysed in  mammals  if  the  blood-supply  to  it  is  stopped.  This  is 
readily  shown  by  Stenson's  experiment  of  gently  compressing 
the  abdominal  aorta  in  a  rabbit  with  the  thumb  or  finger,  so  as 
to  arrest  the  circulation  for  four  or  fire  minutes.  On  releasing 
the  animal  its  hinder  extremities  are  found  to  be  paralysed,  and 
this  paralysis,  though  it  may  be  partly  due  to  interference  with 
the  blood-supply  of  the  muscles  and  nerves  of  the  lower  extremi- 
ties themselves,  is  chiefly  due  to  the  arrest  of  circulation  in  the 
spinal  cord.  The  spinal  cord  in  frogs  is  less  rapidly  affected,  but 
if  the  circulation  be  arrested  for  half  an  hour  or  so  symptoms 
of  paralysis  usually  begin  to  appear,  the  time  varying,  however, 
with  the  temperature  and  other  conditions.  Indirect  paralysis 
is  produced  by  aconitine,  digitalin,  and  large  doses  of  quinine, 
which  arrest  the  circulation.  It  is  frequently  difficult  to  decide 
how  far  paralysis  is  due  to  the  action  of  a  drug  on  the  circulation, 
and  how  far  to  its  direct  action  on  the  spinal  cord  itself. 

Direct  Paralysis.— Paralysis  of  reflex  movement  is  produced 
by  a  number  of  substances,  some  of  which  produce  little  or  no 
previous  excitement ;  others,  however,  markedly  increase  the  ex- 
citability of  the  spinal  cord  first,  and  are  thus  classed  as  spinal 
stimulants. 


chap,  vii.]  ACTION  OP  DEUGS  ON  THE  SPINAL  CORD.    165 

Spinal  Depressants.— The  following  drugs  belong  to  this 
class : — 

Depress  without  marked  previous  Excite  first  and  afterwards  paralyse, 

excitement. 

Antimony.  Ammonia. 

Emetin.  Apomorphine. 

Ergot.  Alcohol  (through  circu- 

Hydrocyanic  acid.  lation. 

Methylconiine.  Arsenic. 

Saponine.  Camphor. 

Physostigmine.  Morphine  group.1 

Turpentine.  Carbolic  acid. 

Zinc,  Chloral. 

Silver.  Nicotine. 

Sodium.  Potassium  salts. 

Lithium.  Veratrine. 

Caesium.  Mercury. 

Alcohol  group1  (action    on 

nervous  substance). 

Uses  of  Spinal  Depressants. — Such  substances  as  morphine, 
chloral,  &c,  which  diminish  the  conducting  power  of  the  grey 
matter  of  the  cord  for  painful  impressions,  are  useful  as  anodynes, 
though  their  action  in  lessening  pain  is  probably  often  due  to 
their  effect  on  the  brain  as  well  as  on  the  spinal  cord.  Spinal 
depressants  which  lessen  reflex  action  are  employed  in  diseases 
where  there  seems  to  be  increased  excitability  of  various  parts  of 
the  cord,  as  evidenced  by  spasm,  either  tonic  or  clonic.  They 
are  therefore  employed  in  tetanus,  trismus  neonatorum,  chorea, 
writer's  cramp,  and  paralysis  agitans.  The  pathology  of  many 
nervous  diseases  is  imperfectly  known,  and  as  the  action  of  spinal 
depressants  is  frequently  a  complex  one  of  combined  stimulation 
and  depression,  some  of  the  drugs  included  in  this  class  are 
used  in  paraplegia  due  to  myelitis,  locomotor  ataxy,  and  general 
paralysis. 

They  are  also  used  as  antagonists  in  cases  of  poisoning  by 
spinal  stimulants  like  strychnine. 

Inhibitory  Paralysis.  —  The  higher  parts  of  the  nervous 
system  have  the  power  of  lessening  the  action  of  the  lower,  and 
in  the  frog  this  power  seems  to  be  especially  marked  in  the  optic 
lobes.  Irritation  of  these  either  mechanically  by  a  needle,  chemi- 
cally by  a  grain  of  salt  laid  upon  them,  or  electrically,  will  lessen 
or  entirely  abolish  the  reflex  action  in  the  cord ;  but  this  again 
returns  when  the  irritation  is  removed,  or  when  its  influence  is 
destroyed  by  cutting  the  cord  across,  below  the  point  of  irritation. 
Tbis  fact  was  discovered  by  Setschenow,  and  thus  parts  of  the 

1  Schmiedeberg,  Arzneimitlellehre,  p.  34. 


166  PHAEMACOLOGy  AND  THEEAPEUTICS.     [sect.  i. 

optic  lobes  concerned  in  this  inhibitory  action  are  known  as 
Setschenow's  centres. 

An  inhibitory  action  appears  to  be  exerted  by  the  cranial 
centres  in  higher  animals  also,  for  McKendrick  observed  that  on 
decapitating  a  pigeon  the  body  lies  comparatively  still  for  a 
second  or  two,  and  then  violent  convulsions  set  in.  If  the  body 
be  held  firmly  during  these  convulsions,  and  a  moderately  strong 
faradaic  current  be  applied  to  the  upper  part  of  the_  spinal  cord, 
the  convulsions  may  be  altogether  arrested  while  it  continues, 
again  commencing  when  it  stops.  In  this  experiment  the  appli- 
cation of  the  current  to  the  cut  end  of  the  cord  is  regarded  as 
supplying  a  stimulus  in  place  of  that  which  would  normally  pass 
downwards  from  the  brain. 

Quinine  causes  great  depression  of  reflex  excitability,  and 
this  was  stated  by  Chaperon  to  be  due  to  the  action  of  the  drug 
on  Setschenow's  centres. 


Fig.  60.  —Nervous  system  of  a  frog,  shoving  the  cerebral  and  optic  lobes,  the  medulla  oblongata, 
and  the  spinal  cord  with  nerre-roots.    The  brain  is  shown  on  a  larger  scale  at  p.  184. 

Almost  immediately  after  injection  of  quinine  into  the  dorsal 
lymph-sac,  the  reflex  excitability  of  the  frog  becomes  very  greatly 
reduced  or  almost  entirely  abolished,  but  if  the  spinal  cord  be  now 
cut  across  at  its  upper  part  just  below  the  medulla  oblongata,  the 
reflex  excitability  becomes  as  great,  or  even  greater,  than  the 
normal. 

This  loss  of  excitability  has  been  ascribed  by  Binz  to  the 
action  of  quinine  on  the  heart,  causing  weakening  of  the  circula- 
tion, and  thus  indirectly  producing  paralysis  of  the  cord.  This 
kind  of  paralysis  does  occur  with  large  doses  and  after  consider- 
able time,  but  it  is  quite  different  from  the  inhibitory  paralysis 
described  by  Chaperon,  which  comes  on  almost  immediately  after 
the  injection  of  the  drug  into  the  lymph-sac,  and  disappears 
immediately  on  section  of  the  cord  below  the  medulla. 

I  have  repeated  Chaperon's  experiments,  and  can  fully  confirm 
their  accuracy.  In  doing  so,  however,  it  struck  me  that  the  result 
was  most  marked  when  a  solution  of  quinine  was  concentrated 
and  somewhat  strongly  acid.  It  therefore  appeared  probable  that 
the  inhibition  was  not  due  to  the  direct  action  of  the  quinine 
upon  Setschenow's  centres  after  it  had  been  carried  to  them  by 
the  blood,  but  only  to  its  reflex  action  upon  them.  It  irritates 
locally  the  sensory  nerves  of  the  lymph-sac  into  which  it  is  in- 


chap,  vii.]  ACTION  OF  DEUGS  ON  THE  SPINAL  CORD.    167 

jected,  and  this  stimulus  being  transmitted  to  the  optic  lobes' 
excites  them  so  that  they  produce  inhibition  of  that  reHex  action 
which  would  usually  occur  in  the  cord  when  the  foot  is  irritated 
by  acid.  On  testing  this  hypothesis  by  injecting  acid  alone  into 
the  lymph-sac,  Mr.  Pardington  and  I  found  that  it  also  caused 
reflex  inhibition  like  that  produced  by  quinine.  We  may  there- 
fore conclude  that  there  is  nothing  special  in  the  action  of  quinine 
upon  the  inhibitory  centres ;  it  merely  acts  like  other  irritants 
on  sensory  nerves.1  Probably  digitalis  and  sanguinaria  also  act 
in  a  similar  way. 

NATURE   OP  INHIBITION. 

Inhibition  and  the  action  of  drugs  on  inhibitory  centres  play 
a  very  important  part  indeed  in  pharmacology,  and  on  the  pre- 
sent hypothesis  they  are  very  puzzling. 

By  inhibition  we  mean  the  power  of  restraining  action  which 
some  parts  of  the  nervous  centres  possess.  At  present  it  is  usually 
supposed  that  certain  parts  of  the  nerve-centres,  instead  of 
having  a  sensory  or  motor  function,  have  an  inhibitory  one 
peculiar  to  themselves.  It  is  found,  however,  that  inhibitory 
powers  are  not  confined  to  Setsehenow's  centres,  already  men- 
tioned (p.  166),  but  that  almost  any  part  of  the  nervous  system 
may  have  an  inhibitory  action  on  other  parts,  so  that  it  becomes 
almost  necessary  to  abandon  the  old  hypothesis.  It  is  found,  for 
example,  that  not  only  is  reflex  action  more  active  in  the  frog 
when  the  optic  lobes  are  removed,  but  that  when  the  spinal  cord  is 
taken  away  in  successive  slices  from  above  downwards,  the  reflex 
action  in  the  part  below  goes  on  increasing.  On  the  old  hypo- 
thesis we  are  almost  obliged  to  assume  that  each  nerve-cell  has 
two  others  connected  with  it,  one  of  which  has  the  function  of 
increasing  or  stimulating,  and  the  other  of  inhibiting  its  action. 
Most  of  the  phenomena  which  we  find  can  be  explained  in  a 
much  simpler  way  by  supposing  that  nervous  stimuli  consist  of 
vibrations  in  the  nerve-fibres  or  nerve-cells,  just  as  sound  cqnsists 
of  vibrations. 


Fig.  61. — Diagram  to  show  increased  intensity        Fig.  62. — Diagram  to  show  abolition  of  vibratiua 
of  vibration  by  coincidence  of  waves.  by  interference  of  waves. 

Interference. — In  the  case  of  both  sound  and  light  we  find 
that  if  two  waves  should  fall  upon  one  another  so  that  their  crests 

1  St.  Bartholomew's  Hospital  Beports,  1876,  p.  155. 


1G8 


PHAEMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 


coincide,  the  intensity  of  the  sound  or  light  is  increased  (Fig.  61), 
•while  if  they  fall  on  each  other  so  that  the  crest  of  one  wave  fills 
up  the  trough  of  the  other,  they  interfere  so  as  to  destroy  each 
other's  effect  (Fig.  62) ;  and  thus  two  sounds  produce  silence,  or 
two  waves  of  light  darkness.  This  is  shown  in  the  case  of  sound 
by  a  tube  (Fig.  63),  which  divides  into  two  branches,  and  these 
again  re-unite.     The  length  of  one  branch  may  be  altered  at 


il= 


— s 

E 


Fhj.  C3. — Diagram  of  apparatus  for  demonstrating  the  interference  of  waves  of  sound.  A  and  B, 
branches  of  a  tube  ;  c,  sliding  piece  by  which  the  branch  B  can  be  lengthened  or  shortened  at 
will ;  d,  tuning-fork ;  B,  the  ear. 

will,  so  that  the  sound  travelling  through  one  branch  has  further 
to  go  than  the  other.  It  may  thus  be  retarded  so  far  as  to  throw 
it  half  a  wave-length  behind  the  other,  and  silence  is  produced. 
If  lengthened  still  further,  so  as  to  throw  the  one  sound  a  whole 
wave-length  behind  the  other,  the  crests  again  coincide,  and  the 
sound  is  again  heard.  Increasing  the  length  still  further,  so  that 
the  one  sound  is  thrown  a  wave-length  and  a  half  behind  the 
other,  they  again  interfere,  and  silence  is  again  a  second  time 
produced.  This  may  be  repeated  ad  infinitum,  silence  occurring 
whenever  Ihe  one  sound  falls  behind  the  other  by  an  odd  number 
of  half  wave-lengths. 


I'ig.  64.— Diagram  showing  the  beats  or  alternate  increase  and  diminution  of  the  wave-heights  by 
the  interaction  of  two  systems  of  waves  of  different  wave-lengths.  At  A,  two  systems,  having  a 
relation  to  each  other  of  3  to  1,  are  indicated  separately  by  dotted  and  complete  lines.  AtB  the 
resultant  of  the  interaction  of  the  two  systems  is  shown.  With  such  a  relation  as  that  shown  in 
the  diagram,  and  with  those  of  a  vibrating  rod  generally,  such  as  n,  Sn,  5n,  &c,  the  interference 
i.f  the  systems. is  not  complete,  and  silence  cannot  be  produced  by  the  interference  of  sounds. 
(iTom  Ganot's  Physics.) 

In  the  case  just  mentioned,  the  waves  are  of  the  same  length, 
but  if  they  are  of  different  lengths,  instead  of  constantly  rein- 


chap,  vii.]  ACTION  OF  DKUGS  ON  THE  SPINAL  COED.    169 

forcing  and  interfering  with  others,  they  may  sometimes  strengthen 
and  sometimes  weaken  each  other.  The  result  is  more  or  less 
rhythmical  increase  and  diminution  of  action,  or  as  it  is  termed 
'  beats.'   This  is  shown  in  the  accompanying  diagram  (Pig.  64). 

Instances  of  rhythm  occur  in  the  body,  which  strongly  remind 
us  of  this  condition ;  for  example,  the  different  rhythms  of  the 
heart  under  various  conditions. 

Interference  in  Nervous  Structures.— Supposing  nervous 
stimuli  to  consist  of  vibrations  like  those  of  light  or  sound,  the 
action  which  any  nerve-cell  would  have  upon  the  others  connected 
with  it  would  he  stimulant  or  inhibitory  according  to  its  position 
in  relation  to  them.  If  its  relation  be  such  that  a  stimulus 
passing  from  it  to  another  cell  will  there  meet  with  a  stimulus 
from  another  quarter  in  such  a  way  that  the  waves  of  which  they 
consist  coincide,  the  nervous  action  will  be  doubled  ;  but  if  they : 
interfere  the  nervous  action  will  be  abolished.  If  they  meet  so 
as  neither  completely  to  coincide  nor  to  interfere,  the  nervous 
action  will  be  somewhat  increased,  or  somewhat  diminished,  ac- 
cording to  the  degree  of  coincidence  or  interference  between  the 
crests  of  the  wave. 

Thus  if  the  relations  of  the  nerve-cells  s,  s'  and  m,  m'  in  the 
diagram  (Fig.  65)  are  such  that  when  a  stimulus  passes  fromja 


Fig.  65.— Diagram  to  illustrate  inhibition  in  the  spinal  cord,  t,  s?,  and  j"  are  sensory  nerves,  m,  m\ 
and  m"  are  motor  nerves,  8,  s',  and  8"  are  sensory  cells,  m,  M',  and  M"  are  motor  cells  in  the  spinal 
cord,  sb  is  a  sensory,  and  MB  a  motor  cell  in  the  brain. 

sensory  nerve  s  to  a  motor  nerve  m,  o"ne  part  of  it  travels  along 
the  path  s,  s,  m,  m,  and  another  along  s,  s,  s',  m, m,  or  s,  s,  s',m',  m,  m, 
at  such  a  rate  that  the  crests  of  the  waves  coincide  at  the  motor 
cell  m,  they  will  increase  each  other's  effect.  If  they  interfere, 
the  effect  of  both  will  be  diminished  or  destroyed,  i.e.  inhibition 
will  occur. 

Effect  of  Altered  Rate  of  Transmission. — But  it  is  evident 
that  the  coincidence  or  interference  of  nervous  stimuli  travelling 
along  definite  nerve-paths,  will  vary  according  to  the  rate  at 
which  they  travel,  so  that  when  stimuli  which  ordinarily  interfere 
with  one  another,  are  made  to  travel  more  slowly,  one  may  be 


170  PHARMACOLOGY  AND  THERAPEUTICS,     [sect,  l 

thrown  a  whole  wave-length,  instead  of  half  a  wave-length,  behind 
the  other  :  and  thus  we  get  coincidence  and  stimulation,  instead 
of  interference  and  inhibition.  "When  stimuli,  whose  waves 
ordinarily  coincide  and  strengthen  each  other's  action,  are  made 
to  travel  more  slowly,  one  may  be  thrown  half  a  wave-length  be- 
hind the  other,  and  thus  we  shall  have  interference  and  inhibition 
instead  of  stimulation. 

On  the  other  hand,  when  the  stimuli  travel  more  quickly,  the 
one  which  was  half  a  wave-length  behind  the  other,  and  interfered 
with  it,  may  be  thrown  only  a  small  fraction  of  a  wave-length 
behind  it.  It  will  thus,  to  a  great  extent,  coincide  and  cause 
stimulation,  while  the  one  which  normally  coincides  with  and 
helps  another  may,  by  travelling  with  increased  rapidity,  get 
half  a  wave-length  in  front  of  the  other,  and  cause  inhibition. 

Opposite  Conditions  produce  Similar  Effects.  —  We  see 
then  that  results,  apparently  exactly  the  same,  may  be  produced 
by  two  opposite  conditions,  increased  rapidity  or  greater  slowness 
of  transmission  of  stimuli. 

The  Same  Conditions  may  cause  Opposite  Effects. — We 
see  also  that  the  same  conditions  may  produce  entirely  opposite 
effects,  by  acting  more  or  less  intensely.  Thus,  the  application 
of  cold,  or  of  any  agent  which  will  render  the  transmission  of 
stimuli  along  nervous  channels  slower  than  usual,  may  throw 
one  which  ordinarily  coincided  with  another  a  small  fraction  of 
a  wave-length  behind  it,  then  half  a  wave-length,  then  three- 
quarters,  next  a  whole  wave-length,  and  then  in  addition  to  the 
whole  wave-length  it  will  throw  it,  as  at  first,  a  small  fraction  or 
a  half  wave-length  behind,  and  so  on. 

We  shall  thus  have  the  normal  stimulation  passing  into  partial, 
then  into  complete  inhibition,  which  will  gradually  pass  off  as 
the  crests  of  the  waves  come  more  nearly  together,  until  they 
coincide,  when  we  shall  again  have  stimulation  as  at  first.  As 
the  action  proceeds,  this  second  stimulation  will  again  pass  into 
inhibition.  In  the  same  way  a  gradual  retardation  of  trans- 
mission will  cause  impulses,  which  normally  interfere,  gradually 
to  coincide  until  inhibition  gives  place  to  complete  stimulation, 
and  this  again  passes  into  inhibition.  By  quickening  the  trans- 
mission and  throwing  one  wave  more  or  less  in  advance  of 
another,  various  degrees  of  heat  will  likewise  produce  opposite 
effects. 

Stimulation  and  Inhibition  on  this  Hypothesis  are  merely 
Consequences  of  Relation.— Stimulation  and  Inhibition  are 
not  due  to  any  particular  stimulating  or  inhibitory  centres ;  they 
are  merely  dependent  on  the  wave-length  of  nervous  stimuli  or 
the  rapidity  of  transmission,  and  on  the  lengths  of  the  paths 
along  which  they  have  to  travel.  Any  nerve-cell  may  therefore 
exercise  an  inhibitory  or  stimulating  action  on  any  other  nerve- 
cell,  and  the  nature  of  this  action  will  be  merely  a  question  of 


chap,  vii.]  ACTION  OF  DRUGS  ON  THE  SPINAL  COED.    171 

the  length  and  arrangement  of  its  connections,  and  the  rapidity 
with  which  stimuli  travel  along  them. 

Test  of  the  Truth  of  the  Hypothesis.— If  the  hypothesis 
be  true  we  ought  to  be  able  to  convert  inhibition  into  stimulation, 
and  vice  vend,  by  either  quickening  or  slowing  the  transmission 
of  stimuli.  We  can  quicken  transmission  by  heat,  and  we  can 
render  it  slower  by  cold. 

On  this  hypothesis  we  would  expect  to  find  that  either  ex- 
cessive quickening  or  excessive  slowing  of  the  passage  of  stimuli 
between  the  cells  of  the  nerve-centres  might  cause  a  number  of 
stimuli  which  would  ordinarily  interfere  to  coincide  and  produce 
convulsions.  This  is  what  actually  does  occur,  for  extreme  heat 
and  extreme  cold  both  cause  convulsions.  But  it  is  unsafe  to 
lay  too  much  stress  upon  this  point,  as  the  cause  of  convulsion 
may  be  very  complex.  We  find,  however,  as  we  should  expect 
on  this  hypothesis,  that  the  inhibitory  action  of  the  vagus  is 
destroyed  by  cold,1 


Explanation  of  the  Actions  of  Certain  Drugs  on  this 
Hypothesis. 

There  are  certain  phenomena  connected  with  the  action  of 
drugs  on  the  spinal  cord  which  are  almost  inexplicable  on  the 
ordinary  hypothesis,  but  which  are  readily  explained  on  that 
of  interference.  Thus  belladonna  when  given  to  frogs  causes 
gradually  increasing  weakness  of  respiration  and  movement,  until 
at  length  voluntary  and  respiratory  movements  are  entirely 
abolished,  and  the  afferent  and  efferent  nerves  are  greatly 
weakened.  Later  still,  both  afferent  and  efferent  nerves  are 
completely  paralysed,  and  the  only  sign  of  vitality  is  an  occasional 
and  hardly  perceptible  beat  of  the  heart,  and  retention  of  irrita- 
bility in  the  striated  muscles.  The  animal  appears  to  be  dead, 
and  was  believed  to  be  dead,  until  Fraser  made  the  observation 
that  if  allowed  to  remain  in  this  condition  for  four  or  five  days, 
the  apparent  death  passed  away  and  was  succeeded  by  a  state  of 
spinal  excitement.  The  fore-arms  pass  from  a  state  of  complete 
flaccidity  to  one  of  rigid  tonic  contraction.  The  respiratory 
movements  reappeared ;  the  cardiac  action  became  stronger,  and 
the  posterior  extremities  extended.  In  this  condition  a  touch 
upon  the  skin  caused  violent  tetanus,  usually  opisthotonic,  lasting 
from  two  to  ten  seconds,  and  succeeded  by  a  series  of  clonic 
spasms.  A  little  later  still  the  convulsions  change  their  character 
and  become  emprosthotonic.  These  symptoms  are  due  to  the 
action  of  the  poison  upon  the  spinal  cord  itself,  for  they  continue 
independently  in  the  parts  connected  with  each  segment  of  the 
cord  when  it  has  been  divided. 

*  Horwath,  Pfillger's  Archiv,  1876,  xii.  p.  278. 


112  PHAKMACOLOGY  AND  THE  KAPEU  TICS,     [sect.  i. 

This  action  may  be  imitated  by  a  combination  of  a  drug  which 
will  paralyse  the  motor  nerves  with  one  which  will  excite  the 
spinal  cord.  Fraser  concludes  that  the  effects  of  large  doses  of 
atropine  just  described  are  due  to  a  combined  stimulant  action  of 
this  substance  on  the  cord,  and  a  paralysing  one  on  the  motor 
nerves.  The  stimulant  action  on  the  cord  is  masked  by  the 
paralysis  of  the  motor  nerves,  and  only  appears  after  the  para- 
lysis has  passed  off.  He  thinks  that  the  difference  in  the  rela- 
tions of  these  effects  to  each  other,  which  are  seen  in  different 
species  of  animals,  may  be  explained  by  this  combination  acting 
on  special  varieties  of  organisation.  In  support  of  his  views  he 
administered  to  frogs  a  mixture  of  strychnine  which  stimulates 
the  spinal  cord,  and  of  methyl-strychnine,  which  paralyses  the 
motor  nerves,  and  found  that  the  mixture  produced  symptoms 
similar  to  thoBe  of  atropine.  Notwithstanding  this  apparently 
convincing  proof,  it  would  appear  that  the  paralysis  in  the  frog 
is  due  to  the  action  of  the  atropine  on  the  spinal  cord,  and  not 
to  a  paralysing  effect  on  the  motor  nerves.  For  Einger  and 
Murrell  have  found  that  when  the  ends  of  the  motor  nerves  in 
one  leg  are  protected  from  the  action  of  the  poison  by  ligature  of 
the  artery  there  is  no  difference  between  it  and  the  unpoisoned 
leg,  while  if  Fraser's  ideas  were  correct  the  unpoisoned  leg  ought 
to  be  in  a  state  of  violent  spasm. 

A  condition  very  nearly  similar  to  that  caused  by  atropine  is 
produced  by  morphine.  "When  this  substance  is  given  to  a  frog, 
its  effects  are  exactly  similar  to  those  produced  by  the  successive 
removal  of  the  different  parts  of  the  nervous  system  from  above 
downwards.  Goltz  has  shown  that  when  the  cerebral  lobes  are 
removed  from  the  frog  it  loses  the  power  of  voluntary  motion, 
and  sits  still ;  when  the  optic  lobes  are  removed  it  will  spring 
when  stimulated,  but  loses  the  power  of  directing  its  movements. 
When  the  cerebellum  is  removed,  it  loses  the  power  of  springing 
at  all ;  and  when  the  spinal  cord  is  destroyed,  reflex  action  is 
abolished. 

Now  these  are  exactly  the  effects  produced  by  morphine,  the 
frog  poisoned  by  it  first  losing  voluntary  motion,  next  the  power 
of  directing  its  movements,  next  the  power  of  springing  at  all, 
and  lastly,  reflex  action.  But  after  reflex  action  is  destroyed  by 
morphine,  and  the  frog  is  apparently  dead,  a  very  remarkable 
condition  appears,  the  general  flaccidity  passes  away,  and  is 
succeeded  by  a  stage  of  excitement,  a  slight  touch  causing 
violent  convulsions  just  as  if  the  animal  had  been  poisoned  by 
strychnine.1 

The  action  of  morphine  here  appears  to  be  clearly  that  of  de- 
stroying the  function  of  the  nerve-centres  from  above  downwards, 
causing  paralysis  first  of  the  cerebral  lobes,  next  of  the  optic 

1  Marshall  Hall,  Memoirs  on  the  Nervous  System,  p.  7  (London,  1837).    Wit- 
kowski,  Archivfiir  exper.  Path,  und  Pharm.,  Band  vii.  p.  247. 


chap,  vii.]  ACTION  OF  DEUGS  ON  THE  SPINAL  COED.    173 

lobes,  next  of  the  cerebellum,  and  next  of  the  cord.  But  it  seems 
probable  tbat  the  paralysis  of  the  cord  first  observed  is  only  ap- 
parent and  not  real ;  and  in  order  to  explain  it  on  the  ordinary 
hypothesis  we  must  assume  that  during  it  the  inhibitory  centres 
in  the  cord  are  intensely  excited,  so  as  to  prevent  any  motor 
action,  tbat  afterwards  they  become  completely  paralysed,  and 
thus  we  get  convulsions  occurring  from  slight  stimuli. 

Ammonium  bromide  also  causes,  first,  complete  loss  of  volun- 
tary movement  and  reflex  action,  but  at  a  later  stage  in  the 
poisoning  convulsions. 

On  the  hypothesis  of  interference,  the  phenomena  produced 
both  by  atropine  and  by  morphine  can  be  more  simply  explained. 
These  drugs,  acting  on  the  nervous  structures,  gradually  lessen 
the  functional  activity  of  the  nerve-fibrils  which  connect  the 
nerve-cells  together ;  the  impulses  are  retarded,  and  thus  the 
length  of  nervous  connection  between  the  cells  of  the  spinal  cord, 
which  is  calculated  to  keep  tbem  in  proper  relation  in  the  normal 
animal  just  suffices  at  a  certain  stage  to  throw  the  impulses 
half  a  wave-length  behind  the  other,  and  thus  to  cause  complete 
inhibition  and  apparent  paralysis. 

As  the  action  of  the  drug  goes  on,  the  retardation  becomes 
still  greater,  and  then  the  impulses  are  thrown  very  nearly,  but 
not  quite,  a  whole  wave-length  behind  the  other,  and  thus  they 
coincide  for  a  short  time,  but  gradually  again  interfere,  and 
therefore  we  get,  on  the  application  of  a  stimulus,  a  tonic  con- 
vulsion followed  by  several  clonic  ones,  and  then  by  a  period  of 
rest.  This  explanation  is  further  borne  out  by  the  fact  observed 
by  Fraser,  that  the  convulsions  caused  by  atropine  occurred  more 
readily  during  winter,  when  the  temperature  of  the  laboratory  is 
low,  and  the  cold  would  tend  to  aid  the  action  of  the  drug  in 
retarding  the  transmission  of  impulses.1 

The  effect  of  strychnine  in  causing  tetanus  is  very  remark- 
able ;  a  very  small  dose  of  it  administered  to  a  frog  first  renders 
the  animal  most  sensitive  to  reflex  impulses,  so  that  slight  im- 
pressions which  would  normally  have  no  effect,  produce  reflex 
action.  As  the  poisoning  proceeds,  a  slight  stimulus  no  longer 
produces  a  reflex  action  limited  to  a  few  muscles,  but  causes  a 
general  convulsion  throughout  all  the  body,  all  the  muscles  being 
apparently  put  equally  on  the  stretch.  In  man  the  form  assumed 
by  the  body  is  that  of  a  bow,  the  head  and  the  heels  being  bent 
backwards,  the  hands  qlenched,  and  the  arms  tightly  drawn  to 
the  body. 

My  friend  Dr.  Ferrier  has  shown  that  this  position  is  due  to 
the  different  strengths  of  the  various  muscles  in  the  body.  All 
being  contracted  to  their  utmost,  the  stronger  overpower  the 
weaker,  and  thus  the  powerful  extensors  of  the  back  and  muscles 

1  Transactions  of  the  Royal  Society  of  Edinburgh,  vol.  xxv.  p.  467. 


174  PHABMACOLOGY  AND  THEEAPEUTICS.     [sect.  i. 

of  the  thighs  keep  the  hody  arched  backwards  and  the  legs  rigid, 
while  the  adductors  and  flexors  of  the  arms  and  fingers  clench 
the  fist  and  bend  the  arms,  and  draw  them  close  to  the  body.1 
The  convulsions  are  not  continuous,  but  are  clonic ;  a  violent 
convulsion  coming  on  and  lasting  for  a  while,  and  then  being 
succeeded  by  an  interval  of  rest,  to  which  after  a  little  while 
another  convulsion  succeeds.  The  animal  generally  dies  either 
of  asphyxia  during  a  convulsion,  or  of  stoppage  of  the  heart 
during  the  interval. 

When  the  animal  is  left  to  itself,  the  convulsions—at  least 
in  frogs— appear  to  me  to  follow  a  certain  rhythm,  the  intervals 
remaining  for  some  little  time  of  nearly  the  same  extent. 

A  slight  external  stimulus,  however,  applied  during  the  in- 
terval—or at  least  during  a  certain  part  of  it — will  bring  on  the 
convulsion.  But  this  is  not  the  case  during  the  whole  interval. 
Immediately  after  each  convulsion  has  ceased  I  have  observed  a 
period  in  which  stimulation  applied  to  the  surface  appears  to 
have  no  effect  whatever. 

It  is  rather  extraordinary,  also,  that  although  touching  the 
surface  produces  convulsions,  irritation  of  the  skin  by  acid  does 
not  do  so.2 

The  cause  of  those  convulsions  was  located  in  the  spinal  cord 
by  Magendie  in  an  elaborate  series  of  experiments,  which  will  be 
described  later  on  (p.  177). 

Other  observers  have  tried  to  discover  whether  any  change 
in  the  peripheral  nerves  also  took  part  in  causing  convulsion  ; 
but  from  further  experiments  it  appears  that  the  irritability  of 
the  sensory  nerves  is  not  increased.3 

According  to  Eosenthal,  strychnine  does  not  affect  the  rate  at 
which  impulses  are  transmitted  in  peripheral  nerves ;  he,  how- 
ever, states  that  it  lessens  the  time  required  for  reflex  actions. 
Wundt  came  to  the  conclusion  that  the  reflex  time  was  on  the 
contrary  increased. 

In  trying  to  explain  the  phenomenon  of  strychnine-tetanus 
on  the  hypothesis  of  interference,  one  would  have  been  inclined 
by  Eosenthal's  experiments  to  say  that  strychnine  quickened  the 
transmission  of  impulses  along  those  fibres  in  the  spinal  cord 
which  connect  the  different  cells  together. 

The  impulses  which  normally,  by  travelling  further  round, 
fell  behind  the  simple  motor  ones  by  half  a  wave-length,  and 
thus  inhibited  them,  would  now  fall  only  a  small  fraction  of  a 
wave-length  behind,  and  we  should  have  stimulation  instead  of 
inhibition. 

Wundt's  conclusion,  on  the  other  hand,  would  lead  to  the 

1  Brain,  vol.  iv.  p.  313. 

2  Eckhard,  Hermann's  Handb.  d.  Physiol.,  Band  ii.  Th.  2,  p.  43. 

3  Bernstein,  quoted  by  Eckhard,  op.  cit.  p.  40.  Walton,  Ludwia's  Arbeiten, 
1882. 


chap,  vn.]  ACTION  OF  DEUGS  ON  THE  SPINAL  COED.    175 

same  result  by  supposing  that  the  inhibitory  wave  was  retarded 
so  as  to  fall  a  whole  wave-length  behind  the  motor  one.  On  the  as- 
sumption, however,  that  the  fibres  which  pass  transversely  across 
from  sensory  to  motor  cells,  and  those  that  pass  upwards  and 
downwards  in  the  cord  connecting  the  cells  of  successive  strata 
in  it,  are  equally  affected,  we  do  not  get  a  satisfactory  explana- 
tion of  the  rhythmical  nature  of  the  convulsions.  By  supposing, 
however,  that  these  are  not  equally  affected,  but  that  the  re- 
sistance in  one— let  us  say  that  in  the  transverse  fibres — is  more 
increased  than  in  the  longitudinal  fibres,  we  shall  get  the  im- 
pulses at  one  time  thrown  completely  upon  each  other,  causing 
intense  convulsion,  at  another  half  a  wave-length  behind,  causing 
complete  relaxation,  which  is  exactly  what  we  find. 

This  view  is  to  some  extent  borne  out  by  the  different  effect 
produced  by  a  constant  current  upon  these  convulsions,  accord- 
ing as  it  is  passed  transversely  or  longitudinally  through  the 
spinal  cord.  Eanke  found  that  when  passed  transversely  it  has 
no  effect,  but  when  passed  longitudinally  in  either  direction 
it  completely  arrests  the  strychnine  convulsions,  and  also  the 
normal  reflexes  which  are  produced  by  tactile  stimuli. 

Eanke's  observations  have  been  repeated  by  others  with 
varying  result,  and  this  variation  may,  I  think,  be  explained  by 
the  effect  of  temperature. 

The  effect  of  warmth  and  cold  upon  strychnine-tetanus  is 
what  we  would  expect  on  the  hypothesis  of  interference.  With 
small  doses  of  strychnine,  warmth  abolishes  the  convulsions, 
while  cold  increases  them.  When  large  doses  are  given,  on  the 
contrary,  warmth  increases  the  convulsions,  and  cold  abolishes 
them.1 

We  may  explain  this  result  on  the  hypothesis  of  interference 
in  the  following  manner : — 

If  a  small  dose  of  strychnine  retard  the  transmission  of  ner- 
vous impulses  so  that  the  inhibitory  wave  is  allowed  to  fall  rather 
more  than  half  a  wave-length,  but  not  a  whole  wave-length, 
behind  the  stimulant  wave,  we  should  have  a  certain  amount  of 
stimulation  instead  of  inhibition.  Slight  warmth,  by  quickening 
the  transmission  of  impulses,  should  counteract  this  effect,  and 
should  remove  the  effect  of  the  strychnine.  Cold,  on  the  other 
hand,  by  causing  still  further  retardation,  should  increase  the 
effect.  With  a  large  dose  of  strychnine,  the  transmission  of  the 
inhibitory  wave  being  still  further  retarded,  the  warmth  would 
be  sufficient  to  make  the  two  waves  coincide,  while  the  cold 
would  throw  back  the  inhibitory  wave  a  whole  wave-length,  and 
thus  again  abolish  the  convulsions. 

The  effect  of  temperature  on  the  poisonous  action  of  guanidine 
is  also  very  extraordinary,  and  is  very  hard  to  explain  on  the 

1  Kunde  and  Virchow,  quoted  by  Eckhard,  op.  cit.  p.  44 ;  Foster,  Journal  of 
Anatomy  and  Physiology,  November  1873,  p.  45. 


176  PHAEMACOLOGY  AND  THERAPEUTICS,     [sect.  I. 

ordinary  hypothesis,  although  the  phenomena  seem  quite  natural 
when  we  look  at  them  as  cases  of  interference  due  to  alterations 
in  the  rapidity  with  which  the  stimuli  are  transmitted  along 
nervous  structures. 

Another  cause  of  tetanus  that  is  difficult  to  understand  on 
the  ordinary  hypothesis  of  inhibitory  centres  is  the  similar  effect 
of  absence  of  oxygen  and  excess  of  oxygen.  When  an  animal  is 
confined  in  a  closed  chamber  without  oxygen,  it  dies  of  convul- 
sions ;  when  oxygen  is  gradually  introduced  before  the  convulsions 
become  too  marked,  it  recovers.  But  when  the  pressure  of  oxygen 
is  gradually  raised  above  the  normal,  the  animal  again  dies  of 
convulsions.  This  is  evidently  not  the  effect  of  mere  increase  in 
atmospheric  pressure,  but  the  effect  of  the  oxygen  on  the  animal, 
inasmuch  as  twenty -five  atmospheres  of  common  air  are  required 
to  produce  the  oxygen-convulsions,  while  three  atmospheres  of 
pure  oxygen  are  sufficient.  This  effect  is  readily  explained  on 
the  hypothesis  of  interference  by  supposing  that  the  absence 
of  oxygen  retards  the  transmission  of  impulses  in  the  nerve- 
centres  ;  so  that  we  get  those  which  ought  ordinarily  to  inhibit 
one  another  coinciding  and  causing  convulsions.  Increased  supply 
of  oxygen  gradually  quickens  the  transmission  of  impulses  until 
the  waves  first  reach  the  normal  relation,  and  then,  the  normal 
rate  being  exceeded,  the  impulses  once  more  nearly  coincide, 
and  convulsions  are  produced  a  second  time.1 

The  effect  of  various  agents  also  in  arresting  or  inhibiting 
muscular  action  suggests  the  possibility  that  such  inhibition  is 
due  to  interference  with  vibrations  in  muscle.  The  vibrations 
of  the  parts  which  occur  in  the  muscle  during  the  passage  of  a 
constant  current  have  already  been  mentioned.  When  a  constant 
current  is  passed  for  a  length  of  time  and  then  stopped,  tetanic 
contraction  of  the  muscle  occurs  and  lasts  for  some  time,  but  it 
can  be  at  once  arrested  by  again  passing  the  constant  current 
through  the  muscle. 

The  idea  that  coincidence  or  interference  of  contractile  waves 
in  muscle  have  much  to  do  with  the  presence  or  absence  of  con- 
traction of  a  muscle  has  been  advanced  by  Kiihne,  in  order  to 
explain  the  phenomenon  observed  by  A.  Ewald.  When  the 
sartorius  of  a  frog  is  stimulated  at  each  end  by  electric  currents 
passing  transversely  through  the  ends,  the  secondary  contraction 
which  can  be  obtained  from  it  is  strongest  in  the  middle  of  the 
muscle,  while  the  points  exactly  intermediate  between  the  middle 
and  the  end  do  not  produce  any  secondary  contraction  at  all. 
This  absence  of  secondary  contraction  Kiihne  thinks  is  due  to 


1  For  other  observations  on  interference  as  a  cause  of  inhibition,  vide  Wundt, 
Untersuchtmgen  sur  Mechanik  cler  Nerven  und  Nervencentren.  1876.'  (Stuttgart : 
T.  Enke) ;  Eanvier,  Lemons  d'Anatomie  Ginerale.  Annie  1877-78.  (Paris  •  J  B." 
Bailliere  et  Fils) ;  and  Lauder  Brunton  '  On  the  Nature  of  Inhibition  and  the' 
Action  of  Drugs  upon  it '  (Nature,  March  1883,  and  reprint). 


chap,  vii.]    ACTION  OP  DEUGS  ON  THE  SPINAL  COED.    177 

interference^  and  the  powerful  secondary  contraction  from  the 
middle  to  coincidence  of  waves.1 

Inhibition  may  also  be  produced  by  direct  irritation  of  in- 
voluntary muscular  fibre.  Thus  I  have  noticed,  under  Ludwig's 
direction,  that  stimulation  of  veins  as  a  rule  very  frequently 
causes  dilatation  at  the  point  of  irritation,  and  if  the  mus- 
cular fibre  of  a  frog's  heart  be  injured  by  pinching  at  one 
point,  that  point  is  apt  to  remain  dilated  when  the  rest  is  con- 
tracted. Protoplasmic  structures  appear  to  be  similarly  affected, 
and  the  passage  of  an  interrupted  current  through  the  heart  of 
a  snail  will  arrest  its  rhythmical  pulsations,  although  the  heart  in 
this  animal  appears  to  be  a  continuous  protoplasmic  structure 
and  destitute  of  nerves.2 

Stimulating  Action  of  Drugs  on  the  Reflex  Powers  of 

the  Cord. 

The  reflex  action  of  the  cord  is  greatly  increased  by  certain 
drugs,  more  especially  by  ammonia  and  by  strychnine.  The 
action  of  strychnine  was  first  investigated  by  Magendie,  and  his 
research  is  not  only  the  first  example  of  the  systematic  investi- 
gation of  the  physiological  action  of  a  drug  leading  to  its  thera- 
peutical employment,  but  is  such  a  model  of  this  method  of 
research  that  it  is  worth  giving  in  detail. 

He  first  introduced  a  little  of  the  upas  poison,  of  which 
strychnine  was  the  essential  ingredient,  under  the  skin  of  the 
thigh  of  a  dog,  and  found  that  for  the  first  three  minutes  no 
symptoms  at  all  were  produced.  Then  the  action  of  the  poison 
began  to  manifest  itself  by  general  malaise,  succeeded  by  marked 
symptoms.  The  animal  took  shelter  in  a  corner  of  the  labora- 
tory ;  and  almost  immediately  afterwards  convulsive  contraction 
of  all  the  muscles  of  the  body  occurred,  the  for.e-feet  quitting  the 
ground  for  a  moment  on  account  of  the  sudden  extension  of  the 
spine.  This  contraction  was  only  momentary,  and  almost  imme- 
diately afterwards  ceased ;  the  animal  remained  calm  for  several 
seconds,  and  was  then  seized  with  a  second  convulsion,  more 
marked  and  prolonged  than  the  first.  These  convulsions  suc- 
ceeded each  other  at  short  intervals,  gradually  becoming  more 
severe.  The  respiration  was  hurried,  the  pulse  quick,  and  it  was 
observed  that  each  time  the  animal  was  touched  a  convulsion 
immediately  followed.  Finally,  death  occurred  at  an  interval 
increasing  with  the  age  and  strength  of  the  animal. 

These  symptoms  suggested  to  Magendie  the  following  ex- 
planation of  the  action  of  the  poison. 

It  was,  he  thought,  absorbed  from  the  wound  into  the  blood, 

1  Untersuchungen  a.  d.  Physiolog.  Inst.,  Heidelberg,  1879.     Sonderabdruck, 
p.  40. 

,2  M.  Foster,  Pflilger's  Archiv. 

■  N 


178  PHARMACOLOGY  AND   THEEAPEUTICS.     [sect.  I. 

by  which  it  was  carried  to  the  heart,  and  thence  to  all  the  organs 
of  the  body.  On  arriving  at  the  spinal  cord,  it  acted  upon  it  as 
a  violent  excitant,  producing  the  same  symptoms  as  mechanical 
irritation  or  the  application  of  electricity.  Magendie  was  not 
content  until  he  had  tested  his  theory  by  experiment.  The  first 
question  to  be  settled  was  whether  the  poison  was  absorbed 
or  not. 

To  test  this  supposition  he  applied  the  poison  first  to  the 
serous  membranes,  the  peritoneum  and  pleura,  from  which,  as 
he  had  learned  by  previous  experience,  absorption  takes  place 
with  extreme  rapidity.  The  result  showed  that  his  supposition 
was  correct.  The  symptoms  appeared  almost  immediately  after 
the  injection  of  the  poison  into  the  pleura,  and  within  twenty 
seconds  after  it  had  been  injected  into  the  peritoneum.  In  order 
to  ascertain  whether  absorption  took  place  from  mucous  as  well 
as  from  serous  surfaces,  he  isolated  a  loop  of  small  intestine  by 
means  of  two  ligatures,  and  injected  a  little  of  the  poison  into 
the  part  between  them.  In  six  minutes,  symptoms  of  poisoning 
appeared,  showing  that  absorption  had  occurred,  but  they  were 
less  intense  than  when  the  poison  was  applied  to  the  serous 
surface. 

Further  experiments  showed  that  absorption  took  place  from 
the  large  intestine,  from  the  bladder,  and  from  the  vagina ;  but 
that  it  was  comparatively  feeble  and  slow.  When  introduced 
into  the  stomach  along  with  food,  upas  invariably  caused  death  ; 
but  the  symptoms  did  not  appear  until  half  an  hour  after  it  had 
been  taken.  This  delay  might  have  been  due  either  to  absorp- 
tion from  the  stomach  having  taken  place  very  slowly  or  not 
at  all,  so  that  the  drug  had  passed  on  to  the  small  intestine,  and 
thence  been  absorbed  into  the  blood.  To  determine  this  point, 
he  isolated  the  stomach  by  ligatures  applied  to  its  cardiac  and 
pyloric  orifices,  and  then  injected  a  little  poison  into  its  cavity. 

Under  such  conditions,  symptoms  of  poisoning  were  only 
observed  after  the  lapse  of  an  hour.  This  showed  that  while 
absorption  from  the  stomach  did  occur,  it  was  much  slower  than 
from  the  small  intestine. 

The  second  question  was,  Does  the  poison  act  through  the 
circulation  ?  If  so,  reasoned  Magendie,  the  first  symptoms  of 
the  action  of  the  poison  will  come  on  more'  slowly  when  it  has 
far  to  travel  to  the  spinal  cord  from  the  point  of  introduction, 
and  vice  versd.  On  testing  this  by  experiment,  he  found  that 
when  the  poison_  was  injected  into  the  jugular  vein,  tetanus 
occurred  almost  instantaneously,  and  death  took  place  in  less 
than  three  minutes,  for  the  upas  had  only  to  pass  through  the 
pulmonary  circulation  and  heart  to  the  arteries  of  the  cord. 
When  injected  into  the  femoral  artery  (at  D,  Fig.  66)  the  dis- 
tance to  be  travelled  before  reaching  the  cord  would  be  greatly 
increased,  for  the  poison  must  first  pass  through  the  artery  itself, 


chap,  vii.]    ACTION  OF  DRUGS  ON  THE  SPINAL  COED.    179 

through  the  capillaries,  and  along  the  vena  cava,  traversing  the' 
whole  distance  marked  D  A  B  in  Pig.  66  before  it  reached  the 
point  where  it  entered  the  circulation  when  it  was  injected  into 
the  jugular.  Under  these  conditions  the  action  should  be  slow, 
and  experiment  showed  this  to  be  actually  the  case,  for  no 
symptoms  appeared  until  seven  minutes  after  the  injection- 
Although  these  experiments  of  Magendie's  appear  to  prove  com- 
pletely that  the  upas  poison  acts  through  the  circulation,  a 
number  of  persons  nevertheless  considered  that  the  symptoms 
were  produced  through  the  nervous  system  by  means  of  so-called 
sympathy.  In  order  to  remove  their  doubts,  Magendie  narcotised 
a  dog  by  means  of  opium,  and  then  divided  all  the  structures  of 
one  leg  with  the  exception  of  the  artery  and  vein.     Into  this 


Eig.  66. — Diagram  illustrating  Magendie's  method  of  investigating  the  mode  of  action  of  upas 
(strychnine).  A,  femoral  vein ;  B,  peritoneum ;  c,  pleura;  D,  femoral  artery;  E,  f,  g,  spinal 
cord,  to  which  small  arteries  are  seen  passing  from  the  aorta.  At  p  is  indicated  a  point  of 
section  of  the  cord. 


almost  isolated  limb  he  then  introduced  a  little  of  the  poison. 
This  was  followed  by  the  usual  symptoms  almost  exactly  as  if 
the  limb  had  been  intact.  By  pressing  upon  the  vein  which 
passed  from  the  limb  to  the  body  when  the  symptoms  of  tetanus 
appeared  he  was  able  to  arrest  their  further  development,  and  by 
releasing  the  vessel  and  allowing  the  circulation  to  have  free 
course  the  symptoms  reappeared.  Lest  by  any  chance  the 
poison  might  have  acted  through  nerves  or  lymphatics  contained 
in  the  walls  of  the  artery  and  vein,  he  divided  these  structures 
also,  connecting  their  several  ends  by  means  of  quills  through 
which  circulation  then  took  place.  When  the  poison  was  applied 
to  the  severed  limb  connected  with  the  body  only  by  these  quills, 
the  same  succession  of  phenomena  occurred  as  when  the  limb 
was  uninjured.  Tho  possibility  of  the  action  being  due  to 
sympathy  between  the  nervous  system  and  the  point  of  applica- 
tion of  the  poison  was  thus  completely  excluded,  and  the  opera- 
tion of  the  poison  through  the  circulation  triumphantly  demon- 
strated. 

The  next  question   was    whether  the   convulsions    were 
caused  by  the  action  of  the  drug  on  the  brain  or  the  cord. 

N   2 


180  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  r. 

To  ascertain  its  action  upon  the  brain,  a  little  of  the  solution 
was  injected  into  the  carotid  artery.  The  effects  produced  were 
the  same  as  those  of  any  irritating  liquid.  The  intellectual 
faculties  disappeared,  the  head  was  laid  between  the  paws,  and 
the  animal  rolled  over  and  over  like  a  ball.  These  effects  passed 
off  as  the  circulating  blood  removed  a  quantity  of  the  drug  from 
the  brain,  and  were  succeeded  by  the  ordinary  tetanic  convulsions 
when  sufficient  time  had  elapsed  for  it  to  reach  the  spinal  cord. 
The  question  whether  it  really  acted  upon  the  cord  still  remained 
to  be  put  to  a  crucial  test.  If  its  effects  were  really  due  to  its 
action  upon  the  spinal  cord  they  ought  to  cease  upon  the  de- 
struction of  that  part  of  the  nervous  system,  and  to  occur  when 
the  drug  was  applied  to  it  alone.  Tbe  cord  was  therefore  de- 
stroyed by  running  a  piece  of  whalebone  down  the  vertebral 
canal  at  the  moment  of  injection.  When  this  was  done,  no 
tetanus  occurred.  In  another  experiment,  Magendie  waited 
until  the  tetanic  spasms  had  been  induced  by  the  upas,  and  then 
destroyed  the  spinal  cord  by  slowly  pushing  the  whalebone  down 
the  vertebral  canal.  As  the  whalebone  advanced,  the  tetanus 
disappeared,  first  in  the  fore-legs,  when  the  dorsal  part  of  the 
cord  was  destroyed,  and  then  in  the  hind-legs,  when  the  whale- 
bone had  reached  the  lumbar  vertebrae. 

In  another  experiment,  an  animal  was  narcotised  by  means 
of  opium,  and  the  spinal  canal  laid  freely  open.  The  upas  was 
then  directly  placed  on  a  part  of  the  spinal  cord.  Tetanus  im- 
mediately occurred  in  that  part  of  the  body,  and  in  that  part 
only  to  which  the  nerves  arising  from  this  portion  of  the  cord 
were  distributed.  When  the  poison  was  successively  applied  to 
other  parts  of  the  cord,  the  convulsions  spread  to  the  correspond- 
ing regions  of  the  body. 

The  question  whether  a  drug  exercises  a  convulsant 
action  through  the  brain  or  spinal  cord  is  now  frequently 
tested,  not  by  destroying  the  whole  cord  as  Magendie  did,  but 
simply  by  dividing  the  spinal  cord  transversely  between  the  occi- 
put and  the  atlas.  Convulsions  depending  upon  stimulation  of 
the  motor  centres  in  the  brain  and  medulla  oblongata  then 
cease  after  section,  while  those  dependent  upon  the  spinal  cord 
do  not. 

The  experiment  of  dividing  the  spinal  cord  transversely  about 
its  middle  is  also  sometimes  performed  in  order  to  test  whether 
the  convulsions  are  of  really  spinal  origin.  If  they  are,  they 
should  persist  in  both  the  anterior  and  posterior  parts  of  the 
body,  but  if  they  are  of  cerebral  origin,  they  occur  in  the  anterior 
but  not  in  the  posterior  part. 

The  effect  of  strychnine  and  allied  substances  upon  the  cord 
is  usually  ascribed  to  increased  excitability  of  the  nerve-cells,  but 
it  is  not  improbably  due  partly  to  alteration  in  the  comparative 
rate  at  which  stimuli  are' transmitted  from  one  cell  to  another  • 


chap.vii.]    ACTION  OF  DEUGS  ON  THE  SPINAL  CORD.    181 

but  this  subject  has  already  been  more  fully  discussed  under 
'  Inhibition '  (q.v.,  p.  173  et  seq.). 

Some  curious  results  obtained  by  Dr.  A.  J".  Spence  may  be 
explained  on  the  latter  hypothesis  which  would  be  inexplicable  on 
the  former.  After  removing  the  blood  from  the  body  of  a  frog, 
and  exposing  the  brain,  he  placed  some  nux  vomica  upon  it,  so 
that  it  could  gradually  diffuse  along  the  spinal  cord.  As  it  passed 
downwards  he  observed  that,  at  first,  irritation  of  the  fore-feet 
caused  spasm  only  in  them ;  later  it  caused  spasm  of  both  front 
and  hind-feet,  while  irritation  of  the  hind-feet  still  produced  the 
ordinary  reflex ;  and  later  still  irritation  of  the  fore-feet  caused 
no  spasm  in  the  hind-legs  while  irritation  of  the  hind-feet  would 
still  cause  spasm  in  the  fore-legs.1 

The  action  of  strychnine  on  the  conducting  power  of  the 
spinal  cord  has  already  been  discussed.  It  diminishes  or 
abolishes  the  power  of  summation,  but  increases  the  reflex 
excitability,  so  that  stimuli  will  produce  reflex  action  which  are 
too  feeble  to  do  so  when  the  spinal  cord  is  in  its  normal  condition. 
The  difference  between  the  reaction  to  strong  and  weak  stimuli 
is  also  to  a  great  extent  abolished,  and  both  produce  tetanic  con- 
tractions. This  condition,  however,  is  absent  for  a  short  time 
after  the  application  of  each  stimulus,  and  then  strong  and  weak 
stimuli  produce  corresponding  strong  and  weak  action,  much  as 
in  the  normal  cord.2 

The  effect  of  nicotine  as  a  spinal  stimulant  is  very  extra- 
ordinary ;  for  Freusberg  found  that  when  frogs  had  been  decapi- 
tated for  twenty-four  hours,  and  reflex  action  was  almost  entirely 
gone,  the  injection  of  a  small  quantity  of  the  poison  increased 
the  reflex  excitability  so  much  that  irritation  of  the  skin  caused 
well-marked  movements.  This  increase  lasted  from  one  to  three 
days,  and  the  bodies  of  frogs  poisoned  by  nicotine  retained  a 
fresh  appearance  for  a  long  time. 

Spinal  Stimulants. 

Spinal  stimulants  are  remedies  which  increase  the  functional 
activity  of  the  spinal  cord. 

Ammonia.  Thebaine. 

Strychnine.  Gelsemine. 

Erucine.  Buxine. 

Absinthe.  Calabarine. 

Nicotine.  Caffeine. 

The  most  marked  of  these  are  strychnine,  brucine,  and  the- 
baine, which  in  small  and  moderate  doses  greatly  increase  the 

1  Edm.  Med.  Journ.,  July  1866. 

*  Ludwig  and  Walton,  Ludwig's  Arbeiten,  1882. 


182  PHARMACOLOGY  AND  THERAPEUTICS.      [sect.  i. 

reflex  excitability,  and  in  large  doses  cause  tetanic  convulsions. 
Besides  these  there  are  some  others,  such  as  opium,  morphine, 
and  belladonna,  which,  although  they  appear  at  first  to  have  a 
sedative  action,  when  given  in  very  large  doses  produce  convul- 
sions. 

Uses. — The  want  of  an  exact  knowledge  of  the  intimate 
pathology  of  diseases  of  the  spinal  cord  renders  the  rational  use  of 
spinal  stimulants  difficult.  They  are  employed  in  the  cases  of 
general  debility  without  any  evidence  of  distinct  disease,  and  in 
paralysis  where  there  is  no  evidence  of  inflammation :  this 
paralysis  may  be  local,  or  affect  the  whole  side  of  the  body,  as  in 
hemiplegia,  or  the  lower  half,  as  in  paraplegia. 

When  strychnine  is  given  in  cases  of  paralysis  until  it  begins 
to  exhibit  its  physiological  action  in  slight  muscular  twitches, 
these  twitches  begin  soooner  and  are  more  marked  in  the  para^ 
lysed  than  the  healthy  parts. 


183 


CHAPTER  VIII. 
ACTION  OF  DEUGS  ON  THE  BRAIN. 

We  are  able  to  judge  to  a  certain  extent  of  the  order  and  kind  of 
action  of  drugs  upon  the  different  parts  of  the  nerve-centres  by 
watching  their  effect  upon  the  movements  of  animals  after  their 
injection. 

Functions  of  the  Brain  in  the  Frog. 

By  removal  of  successive  portions  of  the  nervous  system 
in  the  frog,  Goltz  has  shown  that  the  cerebral  lobes  have  the 
function  of  voluntary  movement,  so  that  when  they  ar.e  removed, 
the  animal  lies  quiet,  unless  acted  upon  by  some  external 
stimulus. 

The  optic  lobes,  which  correspond  to  the  corpora  quadri- 
gemina  of  the  higher  animals,  have  the  function  of  directing  and 
co-ordinating  movements,  but  not  of  originating  them,  so  that  a 
frog  in  which  they  are  uninjured,  but  from  which  the  cerebral 
lobes  have  been  removed,  will  remain  perfectly  quiet,  except  on 
the  application  of  an "  external  stimulus,  when  it  will  leap  like  a 
normal  frog. 

As  the  optic  lobes  have  the  power  of  directing  and  co-ordinat- 
ing movements,  when  they  are  destroyed  the  animal  will  jump, 
but  will  be  unable  to  direct  its  movements. 

The  cerebellum  has  also  the  power  of  co-ordination,  so  that 
when  it  is  removed  the  animal  cannot  jump  at  all,  although  one 
leg  may  answer  by  a  kick  or  other  motion  to  the  application  of  a 
stimulus.  But  even  when  all  those  parts  have  been  removed, 
the  frog  will  still  recover  its  ordinary  position  after  it  has  been 
laid  upon  its  back. 

The  co-ordination  requisite  for  this  power  of  retaining  or 
recovering  its  ordinary  position  appears  to  be  situated  in  the 
medulla  oblongata,  for  when  this  is  removed  the  frog  will  lie 
upon  its  back,  and  will  not  attempt  to  recover  its  ordinary 
position. 

The  legs  will  still  respond  by  movements  to  irritation  applied 
to  the  foot,  but  when  the  spinal  cord  is  now  destroyed  these 
reflex  movements  also  cease. 

In  frogs  poisoned  by  opium,  the  movements  are  gradually 


184  PHARMACOLOGY   AND   THEEAPEUTICS.       [sect.  i. 

abolished  in  the  order  just  mentioned,  and  we  therefore  conclude 
that  opium  affects  the  nerve-centres  in  the  order  of  their  deve- 
lopment, the  highest  being  paralysed  first,  and  the  lowest  last 
(p.  172).  This  order  is  usually  not  quite  the  same  in  higher 
animals,  inasmuch  as  the  last  centre  to  be  paralysed  by  opium 
or  other  anaesthetics  is  usually  the  medulla  oblongata,  and  more 
especially  that  part  of  it  which  keeps  up  the  respiratory  move- 
ments. As  we  shall  afterwards  see,  however,  the  respiratory 
centre  is  really  a  lower  or  more  fundamental  centre  than  either 
the  brain  or  spinal  cord. 

Functions  of  the  Brain  in  Mammals. 

In  higher  animals,  such  as  rabbits  and  guinea-pigs,  the  cere- 
bral hemispheres  are  comparatively  much  more  developed  than 
in  the  frog,  and  their  removal  interferes  very  much  with  the 
animal's  motions.  At  first  it  is  utterly  prostrate,  but  after  some 
time  its  power  of  movement  returns  to  some  extent,  though  it 


Effects  of  removing  the  part  of 
brain  included  in  brackets. 


Voluntary  motion  lost  . 


Cannot  direct  movements 


Cannot  jump   

Cannot  recover  position  when  laid 
on  its  back 


Olfactory  nerves. 
Olfactory  lobes. 


Cerebral  lobes. 
Pineal  gland. 
Optic  thalamus. 
Optic  lobes. 
Cerebellum. 

Rhomboid  sinus. 
Medulla  oblongata. 


Fig.  67. — Diagram  of  the  higher  nerve-centres  of  the  frog. 

remains  much  less  than  in  the  normal  animal.  As  we  should 
expect,  the  weakness  is  most  marked  in  those  parts  of  the  body 
that  are  most  under  the  control  of  the  cerebrum,  and  least  in 
those  whose  movements  are  regulated  by  the  lower  centres. 
Thus  in  rabbits  the  fore-paws  are  capable  of  being  used  for  com- 
plex motions  at  the  will  of  the  animal,  such  as  washing  the  face, 
holding  food,  and  so  on,  and  in  them  the  weakness  caused  by 
removal  of  the  cerebrum  is  much  more  marked  than  in  the  hind 
limbs,  which  are  simply  used  for  progression.  After  the  opera- 
tion the  animal  can  still  stand,  although  it  is  unsteady,  and  the 
fore-legs  tend  to  sprawl  out.  When  pinched  it  bounds  forward, 
but,  unlike  the  frog,  it  is  unable  to  avoid  any  obstacle  in  its  path. 


chap,  viii.]    ACTION  OF  DEUGS  ON  THE  BEAIN. 


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m         -PHARMACOLOGY  AND  THERAPEUTICS,      [sect.  r. 

If  it  be  pinched  at  all  severely,  it  not  only  moves,  but  will  cry 
loudly  and  plaintively,  and  this  condition  is  frequently  noticed  m 
rabbits  under  chloroform,  although  they  have  received  no  injury 
whatever.  The  pupils  contract  on  the  stimulus  of  light,  and  the 
eyes  wink  if  the  finger  is  brought  near  them.  Bitter  substances 
cause  movements  of  the  tongue  and  mouth,  and  ammonia  applied 
to  the  nostrils  may  cause  the  head  to  be  drawn  back,  or  the  animal 
to  rub  its  nostrils  with  its  toes.1 

Where  the  cerebral  hemispheres  are  still  more  developed,  as 
in  cats,  dogs,  and  monkeys,  their  removal  causes  so  much  pro- 
stration, and  interferes  so  greatly  with  motor  power  as  almost 
entirely  to  destroy  equilibrium  and  co-ordinated  progression. 

The  motor  and  sensory  centres  of  the  brain  have  been  more 
exactly  localised  in  monkeys  by  Ferrier,  Fritsch,  Hitzig,  and 
others,  and  the  results  of  their  experiments,  especially  those  of 
Ferrier,  agree  so  well  with  those  of  pathological  observation  in 
men  that  we  may  assume  that  there  is  a  general  agreement 
between  the  position  of  the  centres  in  man  and  monkey. 

The  motor  centres  are  arranged  along  the  two  sides  of  the 
fissure  of  Rolando,  the  order  of  their  arrangement  being  exactly 
what  is  required  for  the  purpose  of  (1)  seeing  food ;  (2)  conveying 
it  to  the  mouth ;  (3)  masticating  it ;  (4)  throwing  away  the 
refuse ;  and  (5)  advancing  to  get  more 2  (vide  Fig.  68,  brain  of 
monkey). 

The  sensory  centres  he  in  the  posterior  and  lower  parts  of 
the  brain.  The  centre  for  sight  is  situated  in  the  angular  gyrus 
and  is  marked  14  and  15  in  the  diagram;  that  for  hearing  is 
situated  in  the  superior  temporo-sphenoidal  and  is  marked  16  in 
the  diagram ;  those  for  smell  and  taste  lie  at  the  tip  of  the 
temporo-sphenoidal  lobe,  and  the  centre  for  general  sensation 
appears  to  be  towards  the  interior  of  the  brain,  in  the  hippo- 
campal  region. 

When  the  motor  centres  in  the  monkey  are  slightly  irritated 
by  a  faradaic  current,  a  single  co-ordinated  movement  is  produced, 
but  if  the  irritation  be  continued  longer,  and  especially  if  a 
strong  current  be  used,  epileptiform  convulsions  may  occur,  suc- 
ceeded by  choreic  movements  after  the  current  has  ceased. 
Epileptic  convulsions  are  easily  produced  by  irritation  of  the 
cerebral  cortex  in  the  cat  and  dog  as  well  as  the  monkey.  It  is 
difficult  to  produce  them  by  cortical  irritation  in  the  guinea-pig 
or  rabbit,  and  impossible  in  birds,  frogs,  and  fishes.3 

1  Ferrier,  Functions  of  the  Brain,  p.  38. 

*  Lauder  Brunton  '  On  the  Position  of  the  Motor  Centres  in  the  Brain  in  regard 
to  the  Nutritive  and  Social  Functions,'  Brain,  vol.  iv.  p.  1. 

*  Francois -Franok  and  Pitres,  Arch,  de  Physiol.,  July  1883,  p.  39. 


chap,  vm.]    ACTION  OF  DRUGS  ON  THE   BKAIN^  187 

Depressant  Action  of  Drugs  on  the  Motor  Centres. 

The  excitability  of  the  brain  may  be  altered  either  by 
conditions  which  modify  the  nerve-cells  or  the  circulation.  A 
deficient  circulation  greatly  depresses  the  excitability,  and  it  is 
very  low  when  much  haemorrhage  has  occurred. 

One  method  of  investigating  the  action  of  drugs  on  the  excita- 
bility of  the  brain  consists  in  trephining  so  as  to  expose  the 
cortical  substance  and  then  stimulating  it  by  a  faradaic  current 
before  and  after  the  administration  of  a  drug  either  by  inhalation 
or  injection.  Another  method  has  been  employed  by  Albertoni, 
who  first  trephines  on  one  side,  and  having  estimated  the 
strength  of  current  sufficient  to  produce  an  epileptic  convulsion 
when  applied  to  a  motor  centre,  he  allows  the  wound  to  heal, 
and  then  gives  for  a  length  of  time  the  drug  on  which  he  wishes 
to  experiment.  He  then  exposes  the  corresponding  motor  area 
on  the  other  side  and  observes  whether  the  strength  of  current 
required  to  produce  an  epileptic  convulsion  is  greater  or  less 
than  before. 

The  excitability  of  the  motor  centres  is  greatly  lowered  by 
anaesthetics,  so  that  as  anaesthesia  becomes  deeper,  irritation  of 
the  motor  centres  has  less  and  less  effect,  and  when  anaesthesia  is 
very  profound,  such  irritation  has  no  action  whatever.1  The 
motor  centres,  however,  are  less  affected  than  the  sensory  ones 
by  anaesthetics,  so  that  they  will  still  react  to  faradaic  irritation 
when  the  sensation  of  pain  has  been  completely  abolished. 

Alcohol  also  diminishes  the  excitability  of  the  motor  centres, 
so  that  the  epileptic  convulsions  which  usually  follow  the  appli- 
cation of  strong  currents  to  the  cortex  are  less  readily  produced 
after  its  administration,  as  well  as  after  ether  and  chloroform.2 
Chloral  for  a  time  diminishes  the  excitability  of  the  brain, 
lengthening  the  latent  period,  so  that  stronger  currents  or  more 
numerous  stimuli  must  be  used  to  produce  a  result :  it  will  tem- 
porarily abolish  the  excitability.  Cold  (not  freezing)  greatly 
lowers  or  destroys  excitability,  and  this  may  be  followed  'by  a 
period  of  increased  excitability  with  a  shorter  latent  period.3 

Bromide  of  potassium,  according  to  Albertoni,  when  given  for 
several  weeks  together,  greatly  diminishes  the  excitability  of  the 
motor  centres,  so  that  when  dogs  are  thoroughly  under  its  in- 
fluence it  is  almost  impossible  to  produce  epileptic  convulsions  by 

1  This  was  observed  in  the  case  of  ether  by  Hitzig,  Vntersuchungen  ilber  das 
GeMrn,  Berlin,  1874.  I  have  had  several  opportunities  of  observing  the  same 
thing  in  regard  to  chloroform  when  assisting  my  friend  Dr.  Ferrier  in  experiments 
on  the  brain. 

2  Francois-Francis  and  Pitres,  op.  cit. 

'  De  Varigny,  Becherches  expirimentaUs  sv/r  I'excitabiUti  ilectrique  des  eircon- 
volutiom  ceribrales  et  sur  lapiriode  d 'excitation  latente  du  cerveau.  Paris,  1884, 
p.  138. 


188     PHARMACOLOGY  AND  THERAPEUTICS.   [sect.i. 

irritation  of  the  cortical  substance.  Atropine  in  small  doses 
increases  the  excitability  of  the  brain  in  monkeys,  but  in  large 
doses  paralyses  it.  It  greatly  increases  the  tendency  to  epileptic 
convulsions  in  dogs,  so  that  they  can  be  produced  by  very  much 
slighter  stimuli  than  usual,  and  strychnine,  absinthe,  and  canna- 
bin  have  a  similar  action  in  this  respect.1  Physostigmine  appears 
to  increase  the  excitability  of  motor  centres  in  the  brain ;  for 
when  guinea-pigs  have  been  rendered  epileptic  by  section  of  a 
sciatic  nerve,  the  administration  of  physostigmine  greatly  in- 
creases the  number  of  fits. 

Irritant  Action  of  Drugs  on  Motor  Centres  in  the 

Brain. 

.Certain  drugs  when  administered  to  animals  or  taken  by 
man  produce  convulsions.  The  muscular  actions  which  occur 
in  these  convulsive  movements  may  be  induced  by  (a)  irritation 
of  the  motor  centres  in  the  spinal  cord,  (b)  the  motor  centres  in 
the  medulla  oblongata  and  pons  Varolii,  or  (c)  cerebral  cortex. 
These  centres  may  be  irritated  directly  by  the  action  of  the  drug 
upon  them,  or  they,  may  be  stimulated  indirectly  by  the  drug 
causing  the  blood  in  them  to  become  venous  through  its  action 
on  the  respiratory  or  circulatory  organs.  Convulsions  of  this 
sort,  although  caused  by  the  administration  of  a  poison,  are 
really  asphyxial,  and  are  similar  in  character  to  those  produced 
by  suffocation. 

Convulsions  are  usually  ascertained  to  be  of  spinal  origin  by 
dividing  the  cord  either  at  the  occiput  or  lower  down  in  its  course 
and  finding  that  they  still  persist  in  those  parts  of  the  body  which 
derive  their  innervation  from  the  spinal  cord  below  the  point  of 
section.  If  they  cease  in  parts  of  the  body  innervated  by  the 
spinal  cord  alone,  but  continue  in  the  parts  which  retain  their 
nervous  connection  with  the  brain,  they  are  regarded  as  of  cerebral 
origin  (v.  p.  179). 

It  has  already  been  mentioned  that  irritation  of  the  motor  areas 
in  the  cortex  of  the  brain  will  produce  epileptic  convulsions,  but 
it  is  probable  that  such  cortical  irritation  acts  through  lower  gan- 
glionic centres  and  especially  through  the  medulla  oblongata  and 
pons  Varolii.  Epileptic  convulsions  can  be  still  more  readily  pro- 
duced by  irritation  of  this  part  of  the  brain  than  by  irritation  of 
the  cerebral  cortex,  and  may  be  induced  by  a  slight  lesion  of  the 
pons  and  medulla  by  a  needle.  It  is  to  irritation  of  this  part  of 
the  brain  by  venous  blood  that  asphyxial  convulsions  are  due,  for 
they  can  still  be  induced  by  suffocation  or  by  ligature  or  compres- 
sion of  all  the  arteries  leading  to  the  brain  after  all  the  parts  of  the 
brain  above  the  pons  have  been  removed,  and  they  cease  when  the 
spinal  cord  is  divided  just  below  the  medulla,  or  the  medulla  itself 

1  Franijois-Franck  and  Pitres,  op.  cik 


ghap.viii.J    ACTION  OF  DEUGS  ON  THE  BEAIN.  189 

divided  at  its  lower  end.  It  is  evident  that,  if  the  spinal  cord  be 
paralysed,  the  convulsions  will  not  occur  though  the  medulla  and 
pons  be  irritated ;  and  it  has  been  found  that,  if  its  blood-supply 
is  stopped  at  the  same  time  as  the  circulation  in  the  pons  by 
ligaturing  the  aorta  in  place  of  the  cerebral  vessels  alone,  convul- 
sions do  not  occur.  Probably  the  absence  of  convulsions  in  slow 
asphyxia  is  due,  at  least  in  some  degree,  to  gradual  paralysis 
of  the  cord  by  the  long-continued  circulation  of  venous  blood 
through  it. 

The  centre  for  convulsions  in  the  frog  appears  to  be  in  the 
medulla  oblongata. 

Asphyxial  convulsions  are  usually  of  an  opisthotonic  charac- 
ter, because,  all  the  muscles  being  stimulated  at  once  by  the  action 
of  the  venous  blood  on  the  motor  centres,  the  stronger  overpower 
the  weaker,  and  the  extensor  muscles  of  the  back  being  more 
powerful  than  the  flexors  bend  the-  spine  backwards.  Asphyxial 
convulsions  only  occur  in  warm-blooded  animals  and  not  in  frogs, 
where  the  respiratory  processes  are  slow,  and  entire  stoppage  of  the 
respiration  for  a  length  of  time  does  not  render  the  blood  suffi- 
ciently venous  to  act  as  a  powerful  irritant.  If  any  drug  therefore 
produces  convulsions  in  the  higher  animals  and  not  in  frogs,  the 
probability  is  that  its  convulsive  action  is  indirect  and  the  convul- 
sions it  produces  are  asphyxial. ..  If,  on-  the  other  hand,.it  produces 
convulsions  in  frogs  as  well  as  higher  animals,  its  convulsive  action 
is  in  all  probability  due  to  the  direct  effect  of  the  drug  upon  the 
nerve-centres.  In  order  to  ascertain  this  definitely,  however,  the 
usual  plan  is  to  see  (1)  whether  the  convulsions  which  occur  after 
the  drug  has  been  injected  disappear  when  artificial  respiration 
is  commenced,  and  (2)  whether  these  convulsions  are  prevented 
by  artificial  respiration  begun  before  the  injection  of  the  drug  and 
kept  up  during  its  action.  But  even  this  does  not  entirely  show 
whether  the  convulsive  action  of  a  drug  is  direct  or  indirect,  for 
artificial  respiration  will  not  prevent  asphyxial  convulsions .  if 
these  should  depend  upon  the  action  of  the  drug  in  stopping  the 
heart  and  thus  arresting  the  circulation.  If  it  is  found  that  the 
convulsions  occur  very  shortly  after  the  heart  stops,  the  usual 
plan  is  -  to  paralyse  the  vagus  in  the  heart  by  atropine,  and 
ascertain  whether  the  convulsive  action  then  occurs.  If  the  drug 
still  produces  convulsions  when  respiration  is  kept  up  and  the 
heart  is  not  stopped,  it  is  almost  certain  that  its  action  is  direct 
upon  the  nerve-centres. 

Experiments  to  ascertain  whether  convulsions  are  asphyxial 
or  not  may  be  conveniently  made  upon  fowls,  for  the  venous  or 
arterial  condition  of  the  blood  is  readily  ascertained  by  the  colour 
of  the  comb. '  Thus,  in  fowls  killed  by  cobra  poison,  the  convul- 
sions come  oh  at  the  moment  the  comb  becomes  livid,  and  when 
artificial  respiration  is  begun  the  convulsions  disappear  as  the 
comb  again  regains  its  normal  colour.     It  is  evident  that  the 


190  PHARMACOLOGY  AND   THERAPEUTICS.      [sect,  i, 

eolour  of  the  comb  will  indicate'  the  condition  of  the  blood  supply- 
ing the  brain,  even  though  a  venous  condition  of  it  should  be  due 
to  stoppage  of  the  heart  and  not  to  failure  of  the  circulation. 

Camphor  has  a  curious  exciting  action  both  upon  the  brain 
and  upon  the  medulla.  It  produces  first  rapid  succession  of  ideas, 
great  desire  to  move,  hallucinations  which  are  generally  agreeable, 
and  a  wish  to  dance  and  laugh.  In  animals  it  has  a  similar 
action,  causing  wild  excitement  and  constant  motion,  succeeded 
by  clonic  epileptiform  convulsions,  during  which  death  often  occurs. 
Usually,  if  they  survive  the  convulsions,  they  recover ;  but  in  man 
the  convulsive  stage  may  be  succeeded  by  paralysis,  coma,  and 
death,  the  parts  of  the  nervous  system  which  are  first  excited 
being  apparently  finally  paralysed.  The  action  upon  frogs  is 
different  from  that  on  warm-blooded  animals,  for  in  them  it  proT 
daces  such  rapid  paralysis  both  of  the  spinal  and  motor  nerves 
that  convulsions  do  not  occur. 

Among  other  drugs  having  a  powerful  convulsant  action  due 
to  irritation  either  of  the  eortical  centres  or  of  the  medulla  and 
pons  are  picrotoxin  (the  active  principle  of  Anamirta  cocculus  or 
Cocculus  indicus),  cicutoxine  (the  active  principle  of  Cicutavirosa), 
and  the  active  principle  of  the  nearly-allied  (Enanthe  crocata, 
coriamyrtin  (from  Coriaria  myrtifolia) ,  digitaliresin  and  toxiresin, 
which  are  products  of  the  decomposition  of  the  active  principles 
of  digitalis. 

The  method  of  localising  the  parts  of  the  brain  upon  which 
certain  drugs  exert  a  convulsant  action,  consists  in  extirpating 
some  of  the  motor  centres  and  then  giving  these  drugs,  such  as 
picrotoxin,  cinchonidine,  and  quinine,1  which  produce  epileptic 
convulsions.2  The  results  of  these  experiments  are  that  the 
epileptic  convulsions  produced  by  these  poisons  appear  to  have  a 
twofold  origin,  (a)  in  the  brain,  and  (b)  in  the  medulla,  the  centre 
in  the  brain  being  the  most  sensitive  to  the  action  of  the  poison. 
In  consequence  of  this,  when  the  poison  is  given  after  the  destruc- 
tion of  the  motor  centres  on  one  side  in  such  quantities  as  not 
to  cause  general  convulsions,  the  weakness  of  the  opposite  side, 
due  to  the  lesions,  becomes  still  more  evident,  probably  from 
the  motor  excitability  of  the  sound  side  being  increased.  When 
convulsions  are  produced  they  are  unsymmetrical.  Those  of  the 
sound  side  are  much  stronger,  are  generally  clonic,  and  appa- 
rently arise  from  irritation  of  the  cerebral  centres.  Those  of  the 
paralysed  side  are  much  weaker,  are  more  tonic,  and  apparently 
arise  from  irritation  of  the  medulla. 


'I  have  seen  a  case  in  which  an  epileptic  convulsion  appeared  to  be  caused  by 
medicinal  doses  of  quinine. 

«  Rovighi  e  Santini,  Publicazioni  del  R.  Inslit.  di  stud,  superiori  in  Firenze 
Sezwne  di  scienze  fisiche  natur.    1882,  s.  1. 


CHAP.vrii.]    ACTION  OF  DEUGS  ON  THE  BRAIN.  191 


ACTION  OF  DRUGS  ON  THE  SENSORY  AND  PSYCHICAL 
CENTRES  IN  THE  BRAIN. 

'The  effect  of  drugs  upon  the  higher  mental  functions  can  only 
be  ascertained  satisfactorily  in  man.  These  functions  vary  in 
complexity  from  simple  choice  to  the  highest  efforts  of  genius. 

The  effect  of  drugs  upon  the  time  required  for  mental  pro- 
cesses is  observed  by  ascertaining,  first,  the  time  required  for 
the  performance  before  and  after  the  administration  of  a  drug, 
and  comparing  these  two  times  with  one  another. 

The  processes  generally  investigated  are,  (a)  the  time  required 
for  simple  reaction ;  (b)  for  discrimination ;  (c)  for  decision.  The 
simple  reaction  is  ascertained  by  marking  on  a  chronograph  the 
time  when  a  signal  is  made,  such  as,  for  example,  the  exhibition 
of  a  coloured  flag.  As  soon  as  this  is  seen  by  the  individual 
experimented  upon  he  marks  the  time  upon  the  same  chronograph 
by  placing  a  finger  upon  a  key  which  is  connected  with  the 
registering  electro-magnet.  The  difference  of  time  between  the 
exhibition  of  the  flag  and  the  time  registered  by  the  electro-magnet 
is  equal  to  the  time  required  for  the  transmission  of  the  sensory 
impulse  to  the  brain,  for  its  transmission  from  the  sensory  to  the 
motor  tracts  of  the  brain,  for  its  passage  down  the  motor  nerves, 
and  the  latent  period  of  the  muscles. 

The  time  required  for  selection  is  ascertained  in  the  same 
way,  but  either  a  red  or  blue  flag  may  be  shown,  and  the  person 
experimented  upon  has  to  discriminate  between  them,  and  only 
to  press  when  the  one  previously  agreed  upon  is  shown.  The 
difference  between  the  time  of  this  experiment  and  the  former 
gives  the  time  required  for  discrimination. 

The  time  required  for  decision  is  ascertained  in  the  same  way 
as  the  previous  one,  excepting  that  a  different  signal  is  to  be  made 
on  the  appearance  of  the  red  and  of  the  blue. 

Simple  reaction  has  been  found  by  Kraepelin '  to  be  little 
affected  by  nitrite  of  amyl :  sometimes  it  is  a  little  quicker  and 
sometimes  a  little  slower  than  normal.  It  is  rendered  slower  by 
aether  and  much  slower  by  chloroform,  although  exceptionally  it 
may  be  quickened  by  chloroform,  probably  when  used  in  small 
doses. 

The  time  required  for  discrimination  is  not  definitely  affected 
by  nitrite  of  amyl,  being  sometimes  increased  and  sometimes 
diminished.  It  is  generally  increased,  though  it  may  be  dimi- 
nished, by  small  doses  of  ether  and  also  by  chloroform. 

The  time  for  decision  is  sometimes  increased  and  sometimes 
diminished  by  nitrite  of  amyl.     It  is  increased  by  ether  and  also 

1  Kraepelin,  Ueber  die  Einwirkung  einiger  medicamentosen  Staff e  auf  die  Dauer 
hinfacher  psychischer  Vprgange,  1882.  Abstract  in  Rivista  Spepmentale  di 
iPrerriatria,  anno  ix.  1888,  p.  124. 


192  PHARMACOLOGY  AND   THERAPEUTICS.       [sect.  i. 

by  chloroform  ;  and  if  the  quantity  given  be  great,  the  increase 
may  be  very  large. 

■  The  influence  of  alcohol  upon  psychical  processes  is  curious  ; 
for  while  it  renders  them  much  slower,  the  individual  under  its 
influence  believes  them  to  be  much  quicker  than  usual. 

Drugs  which  increase  the  Functional  Activity  of  the 

Brain. 

Nerve  Stimulants. 

These  are  remedies  which  increase  the  nervous  activity  of 
the  cerebro-spinal  system.  They  are  subdivided  into  those  which 
act  on  the  cerebrum,  or  cerebral  stimulants,  and  those  which 
affect  the  spinal  cord,  or  spinal  stimulants.  Spinal  stimulants 
have  been  already  discussed  (p.  181) . 

Cerebral  Stimulants. 

In  popular  language,  the  name  of  stimulant  is  generally 
applied  to  drugs  which  have  the  power  to  increase  the  activity  of 
the  brain.  From  their  producing  a  feeling  of  comfort  and  mirth 
they  are  also  called  exhilarants.  The  functional  activity  of  the 
brain,  like  that  of  other  organs,  depends  upon  the  tissue-change 
which  goes  on  in  the  cells  and  fibres  which  compose  it,  and  the 
amount  of  tissue-change  is  regulated  to  a  great  extent  by  the 
quantity  and  quality  of  the  blood  supplied  to  the  organ.  A  free 
supply  of  blood  to  the  brain  may  be  obtained  by  general  excite- 
ment of  the  circulation,  i.e.  more  powerful  and  rapid  action  of 
the  heart  and  contraction  of  the  vessels  in  other  parts  of  the 
body  driving  blood  into  the  brain,  or  by  local  dilatation  of  the 
cerebral  arteries  allowing  blood  more  ready  access  to  the  brain, 
or  by  a  combination  of  these  factors. 

Free  circulation  through  the  cerebral  arteries  may  be  in- 
duced to  some  extent  by  posture  :  thus,  some  men  can  think  best 
when  the  head  is  low,  and  almost  everyone  naturally  assumes 
the  sitting  posture  with  the  head  bowed  down  and  held  between 
the  hands  when  suffering  from  the  effects  of  mental  depression. 
This  posture  is  not,  as  is  often  supposed,  merely  consequent  on 
the  depressed  condition  of  the  nerve-centres,  it  is  voluntarily 
assumed  because  it  affords  an  actual  sense  of  relief.  In  eager 
conversation  also  the  body  generally  stoops  forward  and  the  head 
is  held  low  so  as  to  allow  of  a  free  supply  of  blood  to  the  brain.1 

This  effect  of  posture  on  the  human  brain  is  admirably  shown2 

1  Lauder  Brunton  on  the  Physiological  Action  of  Alcohol,  Practitioner,  1876. 
vol.  xvi.  p.  127. 

*  Francois-Franck  et  Brissaud,  Marty's  Travaux,  1877,  tome  iii.  p.  147. 


chap,  vm.]    ACTION   OP  DRUGS  ON  THE   BRAIN.  198 

by  a  tracing  taken  from  a  patient  with  an  aperture  in  the  skull 
by  b  rancois-Franck  and  Brissaud  (Fig.  69). 


FlG- 69-- Tracing  sh^ig  the  inorease(J  circulation  in  the  brain  caused  bv  inclining  the  head  and 
body  forwards  The  tracing  was  taken  by  Brissaud  and  Francois-Franck,  from  the  parietal  regton 
of  a  woman  who  had  lost  a  large  piece  of  bone  from  syphilis?  "•"<«" ""»  parietal  regum 

Local  dilatation  of  the  arteries  of  the  brain  appears  to  be  pro- 
duced in  animals  by  the  movements  of  mastication  (Fig.  70)  and 
probably  also  by  savoury  food  or  irritating  substances  in  the  mouth. 


AAA 

jOURINC   MASTICATION 


Fio.  70.    Tracing  to  show  the  increased  rapidity  of  circulation  in  the  carotid  of  a  horse  dnrlni. 
mastication..   (After  Marey.)  ^" 

It  is  probably  on  this  account  that  so  many  substances  are  chewed 
for  their  stimulant  action,  such  as  tobacco,  betel  nut,  cola  nut 
and  raisins.  The  effect  of  smoking  is  probably  to  a  great  extent 
due  also  to  its  action  on  the  cerebral  circulation  through  the 
stimulating  effect  of  the  smoke  on  the  nerves  of  the  mouth  and 
nares,  and  so  is  the  use  of  alcohol  in  sips  by  men,  such  as  jour- 


Fig.  71.— Pulsations  of  the  fontanelle  (F)  in  an  inlant  aix  weeks  old  while  sucking,  ti  shows  a 
simultaneous  tracing  of  the  thoracic  respiration.  The  breast  was  offered  to  the  child  at  the 
beginning  of  the  tracing.  At  the  time  indicated  by  the  third  respiratory  wave,  which  has  a 
flattened  top,  the  child  began  to  take  the  breast.  It  will  be  noticed  that  the  line  of  the  tracing 
F  rises,  indicating  increased  circulation  on  the  brain.    (After  Salathc.)a 

nalists,  who  are  engaged  in  writing.     It  is  probable  that  tea  and 
coffee  also  cause  local  dilatation  of  the  arteries  supplying  the 


1  Mareifs  Travaux  for  1877,  p.  147. 

•  SalathS,  Marey's  Travaux,  1876,  p.  354. 


1U  PHARMACOLOGY  AND  THERAPEUTICS,      {sect.  1. 

brain.     Suction  also  causes  an  increased  supply  of  blood  to  the 

brain  (Fig.  71). '  .  ,     ,  ,   •  « 

The  effect  of  local  dilatation  of  the  cerebral  vessels  is  very  greatly 
increased,  if  in  addition  to  it  the  general  circulation  is  increased 
and  the  blood-pressure  raised  by  contraction  of  the  arterioles  in 
the  body  generally,  or  by  more  vigorous  action  of  the  heart. 

General  excitement  of  the  circulation  is  induced  by  exercise 
short  of  fatigue,  and  a  brisk  walk  will  sometimes  remove  a  con- 
dition of  low  spirits.  Sometimes  the  supply  of  blood  to  the  bram 
is  but  slightly  increased  during  continuous  exercise,  as  a  large 
portion  of  the  blood  is  then  diverted  to  the  muscles,  but  after 
the  exertion  is  over  the  excitement  of  the  circulation  continues 
for  some  time,  and  then  the  supply  to  the  brain  is  increased.  In 
some  persons  a  cold  wind  acts  as  an  exhilarant,  causing  con- 
traction of  the  vessels,  with  consequent  increase  in  the  general 
blood-pressure  and  increased  circulation  in  the  brain.  In  persons 
who  are  debilitated  and  feeble,  on  the  contrary,  the  cold  may 
have  an  opposite  effect,  by  depressing  the  action  of  the  heart. 

Some  men  can  think  best  when  walking  about,  on  account  of 
the  excitement  in  the  circulation  which  the  exertion  produces ; 
but  many  such  people,  when  they  come  to  a  very  difficult  point, 
will  stand  still  or  sit  down,  so  as  to  allow  the  blood  to  flow  more 
to  the  head  and  less  to  the  muscles. 

Where  the  circulation  is  feeble,  so  that  the  heart  is  not  much 
stimulated  by  walking  about,  men  often  find  that  they  can  think 
better  when  lying  down,  or  sitting  with  their  head  in  their  hands 
(Fig.  69),  so  as  to  gain  the  advantage  of  the  greater  flow  of  blood 
to  the  head  in  these  positions. 

Stimulation  of  the  mucous  membrane  of  the  nose  by  smelling 
the  vapour  of  strong  ammonia,  carbonate  of  ammonium,  or  acetic 
acid,  raises  the  blood-pressure  generally  throughout  the  body  by 
reflexly  stimulating  the  vaso-motor  centre,  and  thus  increases 
the  circulation  of  blood  in  the  brain.  Smelling  salts  or  aromatic 
vinegar  are  therefore  frequently  employed,  not  only  to  enable 
people  to  attend  more  readily  to  any  subject  in  which  they  are 
engaged,  and  to  prevent  them  from  falling  asleep,  but  also  to 
arouse  them  from  syncope. 

The  action  of  sipping  is  a  powerful  stimulant  to  the  circu- 
lation, for,  as  Kronecker  has  shown,  the  inhibitory  action  of  the 
vagus  on  the  heart  is  abolished  while  the  sipping  continues,  and 
the  pulse-rate  is  very  greatly  increased.  A  glass  of  cold  water 
slowly  sipped  will  produce  greater  acceleration  of  the  pulse  for  a 
time  than  a  glass  of  wine  or  spirits  taken  at  a  draught.  Sipping 
cold  water  has  been  recommended  to  allay  the  craving  for  alcohol 
in  drunkards  endeavouring  to  reform,  and  probably  its  use  is 
owing  to  this  stimulant  action  on  the  heart.  It  is  sometimes 
said  that  a  single  glass  of  ale  sucked  through  a  straw  will  intoxi- 

1  Salathi,  op.  cit. 


chap,  vni.]    ACTION   OF  DEUGS  ON  THE   BBAIN.  195 

cate  a  man,  although  three' times  the  quantity  would  not  do  so  if 
taken  in  large  draughts.  If  this  be  true,  the  more  rapid  intoxi- 
cation caused  by  sucking  is  probably  due  to  the  conjoined  effects 
of  the  alcohol  and  of  temporary  paralysis  of  the  vagus  caused  by 
the  suction,  possibly  aided  by  the  direct  effect  of  suction  on  the 
cerebral  circulation  (Fig.  71,  p.  193). 

One  of  the  most  typical  stimulants  is  alcohol.  In  small 
quantities  it  increases  the  arterial  tension  by  locally  stimulating, 
first  the  sensory  nerves  of  the. mouth,  and  afterwards  those  of 
the  stomach,  and  thus  causing  reflex  contraction  of  the  vessels 
and  reflex  acceleration  of  the  beats  of  the  heart.  This  effect 
occurs  before  its  absorption,  and  is  best  marked  when  the  alcohol 
is  strong,  and  is  but  slightly  marked  when  it  is  diluted.  It  is 
possible  that  by  inducing  local  dilatation  of  the  cerebral  arteries 
while  the  heart  still  continues  active,  it  may  have  a  stimulant 
■  action  on  the  cerebral  functions,  besides  that  which  it  induces  by 
merely  exciting  the  circulation  generally. 

Any  stimulant  action  on  the  brain  beyond  what  may  be 
explained  in  this  way  is  very  slight,  if  indeed  it  exist  at  all. 
Its  further  actions  are  those  of  paralysis  exerted  on  the  nerve- 
centres  in  the  order  of  their  development,  the  higher  centres 
being  paralysed  first  (see  p.  146) . 

At  or  about  this  point  the  stimulating  action  ceases  and  the 
narcotic  action  commences.  The  exhilarating  effect  of  alcohol, 
however,  may  be  most  marked  just  at  this  point,  because  just  here, 
while  the  circulation  in  the  brain'generally  remains  increased,  the 
restraining  or  inhibitory  parts  of  it  begin  to  be  paralysed.  Thus, 
imagination  and  emotion  are  more  readily  excited  and  expression 
is  free  and  unrestrained ;  external  circumstances  are  less  attended 
to,  and  a  boyish  or  childish  hilarity  occurs. 

It  is  probable  that  some  substances,  such  as  strychnine,  in- 
crease the  mental  powers  by  a  direct  action  on  the  brain-tissue 
itself,  and  possibly  caffeine  may  do  so  also. 

Drugs  which  lessen  the  Functional  Activity  of  the 

Brain. 

These  drugs  are  soporifics  or  hypnotics ;  narcotics ;  anodynes 
or  analgesics ;  and  ansesthetics. 

Most  of  the  substances  belonging  to  those  classes  have  a 
certain  resemblance  to  one  another  in  their  action.  Most  of  them 
stimulate  the  mental  functions  when  given  in  very  small  doses. 
In  larger  doses  they  have  also  a  stimulating  action  at  first,  i.e. 
while  a  small  quantity  only  has  been  absorbed,  but  later  on  they 
diminish  or  abolish  the  mental  faculties.  The  same  drug— as, 
for  example,  opium  or  alcohol— in  different  doses  may  thus  act  as 
a  stimulant,  narcotic,  soporific,  and  anesthetic. 

In  a  certain  stage  of  their  action  opium  and  alcohol  do  not 

»  2 


196  PHAKMACOLOGY  AND   THERAPEUTICS.       [sect.  I. 

merely  lessen  the  functional  activity  of  the  brain,  but  they 
disturb  the  normal  relations  of  one  part  to  another,  so  as  to 
produce  disorder  of  the  mental  functions.  Bromide  of  potassium, 
on  the  other  hand,  appears  simply  to  lessen  the  functional  activity 
of  the  brain  without  disturbing  the  relation  of  one  part  to  another. 
We  do  not  know  what  the  causes  of  this  difference  in  their  action 
are,  but  with  some  degree  of  probability  we  may  consider  that  such 
substances  as  bromide  of  potassium,  or  the  normal  products  of 
tissue-waste,  such  as  lactic  acid,  simply  diminish  the  functional 
activity  of  the  nerve-cells  without  disturbing  the  nervous  paths 
by  which  they  communicate  with  one  another,  so  that  we  have 
merely  a  general  and  even  diminution  of  the  mental  faculties,  as 
in  natural  sleep.  Such  substances  as  alcohol,  on  the  other  hand, 
may  be  supposed  not  only  to  diminish  the  functional  activity  of 
the  cells,  but  also  to  disturb  the  rate  at  which  the  impulses  pass 
from  one  cell  to  another,  or  to  alter  the  direction  in  which  these 
impulses  are  sent,  so  that  instead  of  the  mental  activity  being 
lessened  in  degree  but  natural  in  kind,  as  after  the  administration 
of  bromide  of  potassium,  we  have  a  disturbance  of  the  functions 
resembling  that  which  we  find  in  delirium  or  madness. 

Hypnotics  or  Soporifics. 

These  are  remedies  which  induce  sleep.  Although  many  of 
them  are  also  narcotic,  yet  we  may  distinguish  between  hypnotics 
and  narcotics.  Pure  hypnotics  are  substances  which  in  the  doses 
necessary  to  produce  sleep  do  not  disturb  the  normal  relationship 
of  the  mental  faculties  to  the  external  world. 

In  sleep  the  cerebro-spinal  system,  with  the  exception  of  the 
medulla  oblongata,  is  to  a  great  extent  functionally  inactive,  and 
even  the  respiratory  centre  and  the  vaso-motor  centre  in  the 
medulla,  undergo  a  diminution  in  their  functional  activity,  so 
that  the  respiration  becomes  slower,  the  vessels  of  the  surface 
dilate,  and  the  arterial  tension  falls. 

Certain  parts  of  the  nervous  system  may  still  remain  func- 
tionally active,  so  that,  for  example,  when  the  nose  is  tickled 
with  a  hair,  reflex  movements  of  the  face  or  hand  may  occur 
without  awakening  the  sleeper ;  and  certain  parts  of  the  brain 
may  also  be  active  so  that  dreams  occur,  which  may  be  afterwards 
remembered  as  distinctly  as  real  occurrences,  or  may  produce  at 
the  time  various  movements  of  the  body. 

But  while  individual  parts  may  be  active,  the  whole  cerebro- 
spinal system  is  not  active  together,  and  thus  any  co-ordina- 
tion which  may  occur  between  either  sensations  or  motions  is 
incomplete ;  the  dreams  are  incoherent,  and  the  motions  do  not 
affect  the  whole  body,  as  is  seen  in  sleeping  dogs,  where  the  legs 
make  a  movement  of  running,  but  the  animal  continues  to  lie  on 
its  side.     The  functional  inactivity  of  the  whole  or  of  the  greater 


chap,  viii.]    ACTION  OF  DEUGS  ON  THE   BEAIN.  197 

part  of  the  cerebro-spinal  system  is  associated  with  a  condition  of 
anaemia,  and  probably  depends  to  a  certain  extent  upon  it.  At 
the  same  time  it  is  probable  that  sleep  depends  also  on  functional 
inactivity  of  the  cerebral  cells  due  to  accumulation  of  the  products 
of  tissue- waste  in  or  around  them. 

,  The  arteries  of  the  brain  during  sleep  are  contracted,  the  brain 
is  anaemic,  and  its  bulk  is  small.  On  awakening,  the  arteries 
become  dilated,  the  circulation  becomes  rapid,  and  the  brain 
increases  in  bulk.  Where  parts  of  the  brain  are  active,  as  in 
dreaming,  increased  circulation  occurs,  but  probably  this  is  local 
and  not  general. 

In  considering  the  circulation  of  the  brain,  however,  a 
marked  distinction  must  be  drawn  between  the  condition  of  the 
arteries  and  veins.  So  long  as  the  blood  is  in  the  arteries  it  is 
available  for  the  nutrition  of  the  nervous  structures ;  but  once  it 
is  in  the  veins  it  is  no  longer  available,  and  its  accumulation 
there  will  tend  to  impair  nutrition,  both  by  the  pressure  it  exerts 
on  the  nervous  structures,  and  by  its  interference  with  the  supply 
of  arterial  blood. 

In  normal  sleep  the  arteries  and  veins  are  both  contracted, 
and  the  brain  appears  anaemic.  In  the  very  act  of  waking  the 
brain  may  slightly  contract,  and  this  has  been  thought  by  Mosso, 
to  whom  we  owe  the  observation,  to  show  that  sleep  does  not  depend 
upon  anaemia  of  the  brain  ;  but  this  contraction  may  be  due  to 
the  removal  of  venous  blood,  preparatory  to  further  arterial  supply. 

Observations  on  the  brain  by  trephining  appear  to  show  that 
during  ordinary  sleep,  whether  it  has  come  on  naturally,  or  has 
been  induced  by  narcotics,  such  as  a  small  dose  of  opium,  the 
brain  is  anaemic.  During  functional  activity,  either  of  the  whole 
or  of  its  parts,  there  is  arterial  dilatation,  with  a  free  supply  of 
blood.  During  coma  the  veins  become  dilated  and  the  brain  con- 
gested.1 This  congestion,  however,  is  utterly  different  from  the 
arterial  congestion  of  functional  activity,  for  in  coma  the  blood, 
though  abundant  in  quantity,  is  stagnating  in  the  veins,  and 
useless  for  the  tissues. 

In  order  to  produce  sleep,  then,  two  things  are  necessary  : — 

1st.  To  lessen  the  circulation  in  the  brain  as  much  as  possible 
by  diverting  blood  from  it  or  quieting  cardiac  action. 

2nd.  To  lessen  the  functional  activity. of  the  organ. 

Blood  may  be  diverted  from  the  brain  by  dilating  the  vessels 
elsewhere.  In  weak  conditions  of  the  body,  with  feeble  vascular 
tone,  this  may  occur  simply  from  position,  and  such  persons 
become  drowsy  when  standing  or  walking  about,  or  when  sitting. 
As  soon  as  they  lie  down,  however,  the  cerebral  vessels  having 
little  or  no  tone,  the  blood  floods  the  brain,  and  they  are  unable 
to  sleep.    In  such  persons,  sleep  may  be  sometimes  obtained  by 

•  Hammond,  On  Wakefulness,  1866,  p.  20. 


1U8  PHAEMACOLOQY  AND  THEEAPEUTICS.  ;     [seot.u 

raising  the  head  with  high  pillows.  In  such  cases,  also,  vascular 
tonics,  such  as  digitalis,  by  increasing  the  contractile  power  of 
the  arteries  leading  to  the  brain,  may  enable  them  to  resist  the 
increased  pressure  in  the  recumbent  position,  and  thus  prevent 
the  brain  being  flooded  with  blood  and  allow  sleep  to  be  obtained. 


3?ig.  72. — Tracings  from  the  brain  of  a  dog  after  trephining,  showing  the  innuence  of  position  on 
the  cerebral  circulation.  In  the  upper  tracing  the  vertical  line  shows  when  the  head  of  the 
dog  was  lowered,  and  in  the  lower  tracing  when  the  head  was  raised.    (Salathe./  - 

The  largest  vascular  area  into  which  the  blood  may  be  drawn 
away  from  the  brain  is  that  of  the  intestinal  canal.  When  the 
vessels  in  the  intestine  are  contracted,  it  is  almost  impossible  to' 
obtain  sleep.  Consequently  both  man  and  animals,  when  ex- 
posed to  cold,  which  acting  through  the  thin  abdominal  walk 
would  cause  contraction  of  the  intestinal  vessels  and  drive  the 
blood  to  the  brain,  instinctively  keep  the  intestines  warm  by 
curling  themselves  up  before  going  to  sleep,  and  thus  covering 
the  abdomen  with  the  thick  muscles  of  the  thighs. 

Warmth  to  the  abdomen  by  means  of  a  large  poultice  out-; 
side  will  also  tend  to  produce  sleep ;  or,  in  place  of  a  poultice,  a .' 
wet  compress,  consisting  of  linen  or  flannel  wrung  out  of  cold 
water,  and  covered  with  oil-silk,  and  with  two  thicknesses  of  dry 
flannel  placed  above  it,  tends  greatly  to  induce  sleep  and  is  most 
useful  for  this  purpose,  especially  in  children. 

Warmth  to  the  interior  of  the  stomach  has  a  somewhat 
similar  action,-  but  it  differs  from  warmth  to  the  exterior  in 
this,  that  it  may,  to  a  certain  extent,  stimulate  the  heart  as 
well  as  dilate  the  abdominal  vessels.  Stimulation  of  the  heart ' 
is  of  course  objectionable,  as  it  tends  to  maintain  the  activity 
of  the  brain. 

On  this  account  the  food  or  drink  should  be  tolerably  warm, 
but  not  very  hot.  Warm  milk,  either  alone,  or  with  bread 
soaked  in  it,  warm  gruel,  thin  corn-flour,  or  ground  rice,  sago, 
or  tapioca,  warm  beef-tea  or  soup,  or  a  glass  of  hot  wine  and 
water  or  spirits  and  water  at  bed-time,  may  all  act  as  soporifics 
by  withdrawing  the  blood  from  the  brain  to  the  stomach.  In  the 
sleeplessness  of  fever  a  wet  pack,  by  restraining  the  movements 
and  by  diverting  blood  from  the  brain  to  the  body  generally,  is 
often  an  efficient  soporific. 


Marey's  Travaux,  1876,  p.  397. 


chap,  vin.]    ACTION  OP  DEUGS  ON  THE  BEAIN.  199 

Cold  feet  also  tend  to  keep  up  the  tension  in  the  vessels 
and  prevent  sleep,  and  therefore  they  ought  to  be  warmed  either 
by  the  use  of  an  india-rubber  bag  filled  with  hot  water,  and 
covered  with  flannel,  or  by  rubbing  them  briskly  in  cold  water 
and  drying  them  thoroughly  before  going  to  bed,  or  by  both 
means  combined. 

Cardiac  excitement  may  be  lessened  by  sedatives,  one  of 
the  most  useful  of  which  is  cold.  After  hours  of  weary  tossing 
sleep  may  sometimes  be  induced  by  walking  about  in  a  night- 
dress until  cool,  or  by  sponging  the  surface  either  with  cold  or 
hot  water. 

The  chief  hypnotics  or  soporifics  are — 

Opium.  Hypnone. 

.  Morphine.  Bromide  of  potassium. 

Chloral-hydrate.  Bromide  of  sodium. 
Butyl-chloral-hydrate  (croton-     Bromide  of  calcium. 

chloral) .  Bromide  of  zinc. 

Hyoscyamus.  Monobromo-camphor. 

Cannabis.  Hop. 

Paraldehyde.  Lettuce. 

Urethane.  Lactic  acid. 

The  most  powerful  hypnotics  that  we  possess  are  undoubtedly 
opium  and  morphine,  and  they  seem  to  act  by  depressing  the 
functional  activity  of  the  brain  itself,  although  along  with  this 
depression  an  anaemic  condition  of  the  organ  sets  in.  Besides 
their  action  in  producing  sleep,  even  in  health  opium  and  mor- 
phine have  the  power  of  lessening  pain  and  thus  removing  the 
effect  which  painful  stimuli  have  in  maintaining  a  wakeful  con- 
dition.. Bromide  of  potassium  and  bromide  of  ammonium  in 
large  doses  have  also  a  hypnotic  action,  and  even  in  smaller 
doses,  when  they  would  not  of  themselves  produce  sleep,  they 
appear  to  lessen  cerebral  excitement,  and  allow  sleep  to  come  on 
when  other  conditions  are  favourable.  Chloral  probably  causes 
sleep  both  by  acting  on  the  brain  itself  and  by  causing  dilatation 
of  the  vessels  generally.  It  is  therefore  a  useful  hypnotic  in 
persons  suffering  from  Bright 's  disease,  in  which  there  is  high 
tension  of  the  vessels  and  consequently  a  tendency  to  sleeplessness. 

A  combination  of  hypnotics  sometimes  answers  much  better 
than  any  one  singly.  Thus  morphine  or  opium  alone  some- 
times simply  cause  excitement ;  but  when  chloral  is  given,  either 
along  with,  or  after  them,  the  excitement  is  quieted  and  sleep 
occurs. 

A  combination  also  of  small  quantities,  such  as  five  or  ten 
minims,  of  solution  of  opium  or  morphine  with  five  grains  of 
chloral  and  ten  to  thirty  of  bromide  of  potassium,  is  sometimes 
more  useful  than  any  one  of  the  three  used  alone. 

Indian  hemp  also  is  sometimes  used  to  procure  sleep,  and 


200  THAKMACOLOGY  AND   THEEAPEUTICS.       [sect.  I; 

lettuce  and  lactucarium  are  also  said  to  have  a  hypnotic  action. 
Lettuce  certainly  does  seem  to  have  such  an  action,  hut  how 
much  of  it  depends  upon  the  juice  and  how  much  upon  the 
mechanical  effect  of  the  indigestible  fibres  of  the  lettuce  upon 
the  stomach,  in  drawing  blood  to  it,  it  would  be  hard  to  say. 
Hops  are  said  to  be  hypnotic,  and  their  combination  with  lettuce 
in  the  form  of  a  supper  consisting  chiefly  of  beer  and  salad  has 
sometimes  a  very  marked  soporific  action. 

Narcotics. 

Narcotics  are  substances  which  lessen  our  relationships  with 
the  external  world.  They  are  closely  related,  as  I  have  already 
stated,  to  stimulants ;  and  alcohol  in  the  various  stages  of  its 
action  affords  us  a  good  example  of  both  stimulant  and  narcotic 
action.  Alcohol  at  first  excites  the  cerebral  circulation  and  then 
begins  to  paralyse  various  parts  of  the  brain  in  the  inverse  order 
of  their  development. 

But  this  order  differs  in  different  individuals ;  for  in  watching 
the  growth  of  children  we  find  that  the  order  of  development  of 
the  nerve-centres  in  them  is  not  always  the  same :  some  talking 
before  they  can  walk,  and  others  walking  before  they  can  talk. 
In  all,  however,  the  powers  of  judgment  and  self-restraint  are 
among  the  last  to  be  completely  developed. 

While  the  circulation  of  the  brain  is  still  active,  the  restrain- 
ing or  depressing  effect  of  present  external  circumstances,  and 
the  restraining  effect  of  training,  during  previous  life,  which  are 
stored  up  as  it  were  in  the  inhibitory  centres,  are  lessened.  The 
fancy  is  thus  allowed  free  play  and  a  condition  of  joyousness  and 
volubility  like  that  of  a  child  occurs.  The  imagination  and 
memory  fail  next  in  some,  while  the  emotions  become  prominent, 
and  to  this  follows  paralysis  or  paresis  of  the  power  of  co-ordina- 
tion. In  others  the  power  of  co-ordination  is  impaired  before 
the  mental  faculties  are  much  affected,  the  speech  becomes  thick 
and  the  walking  becomes  staggering  and  uncertain.  At  this 
stage  reflex  action  still  persists,  but  afterwards  it  is  diminished, 
then  abolished,  and  finally  paralysis  of  the  respiratory  centre 
occurs.  The  effect  of  other  drugs,  such  as  ether  and  chloroform, 
is  much  the  same  as  that  of  alcohol. 

In  the  case  of  opium  and  Indian  hemp,  however,  there  is  but 
little  excitement  of  the  circulation,  and  their  effects  appear  to  be 
due  more  to  alterations  in  the  relative  functions  of  the  different 
parts  of  the  brain. 

Belladonna,  hyoscyamus,  stramonium,  and  their  allies,  have 
a  curious  effect.  They  produce  delirium  of  an  active  character, 
the  patient  having  a  constant  desire  to  speak,  move  about,  or  be 
doing  something,  while  at  the  same  time  he  feels  great  languor. 
It  is  probable  that  this  effect  is  due  to  the  combined  stimulant 


chap,  viii.]     ACTION  OF  DKUGS  ON   THE   BKAIN. 


201 


action  of  these  drugs  on  the  nerve-centres  in  the  brain  and 
spinal  cord  and  their  paralysing  action  on  tjie  peripheral  ends  of, 
motor  nerves. 

Anodynes  or  Analgesics. 

Anodynes  are  remedies  which  relieve  pain  by  lessening  the 
excitability  of  nerves  or  of  nerve-centres.  They  are  divided  into 
local  or  general : — 

Local  Anodynes.  General  Anodynes. 


Anaesthetics  in  small  doses. 

Atropine. 

Belladonna. 

Butyl-chloral. 

Chloral. 

Conium. 

Coniine. 

Gelsemium. 

Hyoscyamus. 

Hyoscyamine. 

Lupulus. 

Lupulin. 

Morphine. 

Opium. 

Stramonium. 


Cold- 
Cold  water. 
Ice-bags. 

Warmth — 
Poultices. 
Fomentations. 

Aconite. 

Acupuncture. 

Atropine. 

Belladonna. 

Blood-letting — 
Leeches. 
Cupping. 

Carbolic  acid. 

Carbonic  acid. 

Cocaine. 

Conium. 

Creasote. 

Gelsemium. 

Hydrocyanic  acid. 

Morphine. 

Opium. 

Veratrine. 

Action. — The  sensation  of  pain  is  due  to  a  change  in  some 
part  of  the  cerebrum,  and  is  usually  excited  by  injury  to  some 
part  of  the  body. 

According  to  Ferrier  the  hippocampal  region  is  the  seat  of 
sensation.  Pain  may  be  of  central  origin ;  for  if  these  convo- 
lutions should  from  any  cause  undergo  changes  similar  to  what 
.usually  take  place  in  them  on  the  application  of  a  painful 
stimulus  to  a  nerve,  pain  will  be  felt,  even  although  no  injury 
whatever  has  been  done  to  the  body.  Something  of  this  sort 
appears  to  occur  in  certain  cases  of  hysteria. 

Conversely,  if  the  changes  which  ordinarily  occur  in  these 
.convolutions  on  severe  irritation  of  a  sensory  nerve  are  prevented 
from  taking  place,  pain  will  not  be  felt,  however  great  the 
stimulus  to  the  nerve  may  be. 

The  sensory  nerves  of  the  head  pass  directly  to  the  brain,  but 


202  PHAEMACOLOGY  AND  THERAPEUTICS.      [sect.  x. 

all  other  sensory  nerves  have  to  pass  fora  greater  or  less  distance 
along  the  spinal  cord  before  they  reach  the  brain. 

The  transmission  of  painful  impressions  along  the  spinal  cord 
occurs  in  the  grey  matter,  and  the  effect  of .  anaesthetics  in  pre- 
venting the  transmission  of  painful  impressions  while  tactile 
stimuli  are  still' conducted  has  been  already  discussed, 
i  •  Pain  may  be  occasioned  by  irritation  applied  to  nerves  any* 
where  between  the  brain  and  the  periphery ;  and  whatever  its 
point  of  application  may  be,  it  is  usually  referred  to  the 
peripheral  distribution  of  the  nerve.  Sometimes  irritation 
of  a  nerve,  instead  of  being  referred  by  the  brain  to  the  proper 
spot,  is  referred  to  a  branch  of  the  same  nerve  going  to  a 
different  point. 

Pain  may  be  caused  by  violent  stimulation  of  the  peripheral 
distribution  of  a  nerve,  of  its  trunk,  of  the  spinal  cord  through 
which  the  fibres  pass  to  the  brain,  or  of  the  encephalic  centres 
themselves. 

Pain  may  be  relieved  by  (a)  removing  the  source  of  irritation, 
(b)  by  preventing  the  irritation  from  affecting  the  cerebrum. 
Thus,  if  necrosis  of  the  jaw  should  give  rise  to  intense  pain,  the 
pain  will  at  once  cease  on  dividing  the  sensory  nerve  by  which 
the  impulses  are  transmitted  to  the  brain.  It  may  be  relieved, 
also,  while  the  source  of  irritation  still  remains,  by  lessening  the 
excitability  of  the  peripheral  terminations  of  the  sensory  nerves 
which  receive  the  painful  impression ;  or  of  the  nerve-trunks ;  or 
of  the  spinal  cord  along  which  the  impression  travels ;  or  of  the 
cerebral  centres  in  which  it  is  perceived. 

Opium  probably  acts  on  them  all,  diminishing  the  excitability 
of  the  cerebral  centre,  of  the  spinal  cord,  and  of  the  sensory 
nerves ;  and  bromide  of  potassium  is  also  supposed  to  affect  all 
these  structures,  though  to  a  much  less  degree  than  opium. 

Chloral,  butyl-chloral,  lupulin,  gelsemium,  and  cannabis 
indica  probably  act  on  the  cerebral  centres. 

Belladonna  and  atropine  lessen  the  excitability  of  the  sensory 
nerves,  and  probably  this  is  effected  also  by  hyoscyamus,  stra- 
monium, aconite,  aconitine,  and  veratrine. 

Uses.— It  is  evident  that  if  the  nerve-centre  by  which  pain  is 
perceived  is  deadened,  the  pain  will  cease  wherever  its  seat  may 
be ;  and  therefore  opium  and  morphine  are  used  to  relieve  pain 
Whatever  may  be  its  cause.  Cannabis  indica  and  bromide  of 
potassium,  having  likewise  a  central  action,  may  also  be  em- 
ployed, but  they  are  very  much  less  efficient  than  opium. 
Chloral  and  butyl-chloral  have  an  anaesthetic  action  when  given 
in  very  large  doses,  but  in  moderate  doses  their  power  to  relieve 
pain  is  not  so  marked  as  their  hypnotic  action.  Butyl-chloral, 
however,  seems  to  have  a  special  sedative  action  on  the  fifth 
nerve,  and  so  has  gelsemium :  consequently  both  of  them  are 
used  in  the  treatment  of  facial  neuralgia. 


chap,  viii.]    ACTION  OF  DRUGS  ON  THE   BRAIN.  203 

As  cocaine,  belladonna,  aconite,  and  veratrine  have  a  local 
action  on  the  peripheral  ends  of  the  sensory  nerves,  they  are 
usually  applied  directly  to  the  painful  part  in  the  form  of  lotion, 
ointment,  liniment,  or  plaster.  Local  injections  of  cocaine,  mor- 
phine, atropine,  or;  ether,  in  the  neighbourhood  of  the  painful 
part,  are  often  of  the  greatest  service. 

Adjuncts  to  Anodynes.— As  pain  depends  on  the  condition 
of  the  cerebral  centre  by  which  it  is  perceived,  as  well  as  on 
irritation  of  sensory  nerves,  it  is  obvious  that  it  may  vary  with 
the  condition  of  these  centres,  although  the  irritation  remains. 
Thus  a  decayed  tooth  does  not  always  cause  toothache,  and  when 
the  toothache  comes  on,  it  may  frequently  be  removed  by  means 
of  a  brisk  purgative,  even  although  the  tooth  be  not  extracted. 
It  is  possible  that  the  purgative  may  act  partly  by  lessening  con- 
gestion around  the  tooth,  but  partly.also  by  altering  the  condition 
of  the  cerebral  centres.  When  the  attention  is  fixed  upon  other 
things,  also,  the  pain  may  be  to  a  great  extent,  or  even  com- 
pletely, abolished,  as  in  mesmerism  or  hypnotism.  The  sensory 
stimuli,  also,  which  would  usually  produce  pain  may  be  diverted 
voluntarily  or  involuntarily  into  motor  channels.  Thus,  during 
the  heat  of  action,  the  pain  of  a  wound  is  not  felt ;  and  the  pain 
felt  during  the  extraction  of  a  tooth  is  lessened  by  the  employ- 
ment of  violent  muscular  effort,  as  in  grasping  the  arms  of  the 
dentist's  chair.  Other  most  powerful  adjuncts  are  electricity 
applied  along  the  course  of ,  the  nerves,  and  counter-irritation, 
especially  by  means  of  the  actual  cautery  to  the  painful  part, 
and,  when  other  means  fail,  stretching  the  nerve  may  succeed. 

Cold  also,  applied  to  the  surface  over  a  painful  part,  will 
relieve  pain,  and  so  may  dry  heat,  applied  by  a  sand-bag  or  hot 
cloth,  or  moist  heat  in  the  form  of  a  poultice ;  for  the  mode  of 
action  of  these  vide  '  Action  of  Iebitants.' 

Pain  has  been  ascribed  by  Mortimer  Granville  to  vibrations 
of  nerves  or  of  the  sheaths;  and,  in  order  to  lessen  it,  he  pro- 
poses to  produce  vibrations  of  a  different  nature :  this  he  does  by 
percussing  over  the  painful  nerve  with  a  small  hammer,  worked 
either  by  clockwork  or  electricity.  For  a  dull  heavy  pain  he 
uses  quick  and  short  vibrations  of  the  hammer,  and  for  a  sharp 
lancinating  pain  he  uses  large  and  slow  vibrations. 

Anaesthetics. 

Anaesthetics  are  remedies  which  destroy  sensation. 

It  has  already  been  mentioned  that  both  sensation  and  pain 
require  for  their  perception  a  certain  condition  of  the  cerebral 
centres  and  of  the  sensory  nerves  and  spinal  cord,  by  which 
impressions  are  conveyed  to  these  centres. 

The  difference  between  anaesthetics  and  anodynes  is  to  a  great 
extent  one  of  degree.     Anodynes  affect  more  particularly  the 


204  PHAKMACOLOGY  AND   THEBAPEUTICS.  ,     [sect.  i. 

cerebral  centres  by  which  pain  is  perceived,  or  the  conducting 
paths  by  .which  painful  impressions  are  transmitted,  and  thus 
in  moderate  doses  lessen  pain  without  destroying  reflex  action. 
They  only  affect  the  ordinary  centres  for  reflex  action  when  the 
dose  is  considerably  increased.  Anaesthetics,  on  the  other  handi 
affect  the  cerebral  and  spinal  centres  more  equally,  and  so  abolish 
pain,  ordinary  sensation,  and  reflex  excitability  more  nearly  at 
the  same  time,  though  their  abolition  is  by  no  means  completely 
simultaneous. 

According  to  Eulenberg,  in  chloroform-narcosis  the  patellar 
reflex  is  abolished  first,  then  reflex  from  the  skin,  then  from  the 
conjunctiva,  and  lastly  from  the  nose.  As  the  anaesthesia  passes 
off  they  return  in  the  inverse  order,  patellar  reflex  being  the  last 
to  reappear.  A  stage  of  excitement  generally  precedes  the  dis- 
appearance of  patellar  reflex,  both  in  man  and  animals. 

Narcosis  by  ether  differs  from  that  of  chloroform  in  the  much 
greater  increase  of  patellar  and  other  tendon  reflexes,  both  in 
extent  and  duration. 

Chloral  hydrate  and  potassium  bromide  have  an  action  like 
chloroform,  but  much  weaker.  Like  chloroform,  they  paralyse  the 
patellar  reflex  before  the  corneal  reflex,  but  butyl-chloral  (croton- 
chloral)  paralyses  the  corneal  reflex  before  the  patellar. 

In  ordinary  sleep,  reflexes  disappear  in  the  same  order  as  in 
chloroform  narcosis,  but  in  mesmeric  sleep  the  reflexes  are  in- 
creased as  in  narcosis  from  ether.  In  hysterical  conditions 
diminution  of  the  cerebral  reflexes  from  the  nose  and  cornea 
with  persistence  of  the  patellar  reflex  has  been  observed. 

The  reflex  power  of  the  vaso-motor  centre  is  very  quickly 
paralysed  by  chloroform,  so  that  irritation  of  a  sensory  nerve 
will  no  longer  raise  the  blood-pressure.  Its  reflex  power  is  much 
less  affected  by  ether.1 

Anaesthetics  may  be  divided  into  local  and  general.  The 
local  are  those  which  abolish  the  sensibility  of  the  peripheral 
nerves  of  a  particular  area.  The  general  are  those  which  act 
on  the  central  nervous  system  in  the  way  already  described,  and 
abolish  sensation  throughout  the  whole  body. 

The  chief  local  anaesthetics  are  cold,  cocaine,  carbolic  acid, 
iodoform. 

For  the  purpose  of  producing  local  anaesthesia,  cold  is  generally 
applied  by  means  of  ether  spray,  until  the  part  is  all  but  frozen 
and  is  insensible,  when  slight  operations  may  be  made  without 
the  patient  feeling  any  pain.  The  ether  may  perhaps  have  itself 
a  certain  amount  of  physiological  effect  in  diminishing  sensibility 
when  applied  in  this  manner.  Carbolic  acid  painted  over  the  sur- 
face also  causes  it  to  become  white  and  to  lose  its  sensibility,  and 
may  thus  be  used  to  lessen  the  pain  of  opening  an  abscess. 


*  H.  P.  Bowditoh  and  C.  S.  Minot,  Boston  Med.  and  Swg.  Journ.,  May  21, 1874. 


chap,  vin,]    ACTION   OF  DEUGS   ON   THE   BRAIN.  205 

General  anaesthetics  are- 
Nitrous  oxide.  Trichlorhydrin. 
Ether.  Bi-chloride  of  methylene. 
Chloroform.  Paraldehyde. 
Bromoform.  Bi-chloride  of  ethidene. 
Tetrachloride  of  carbon.  Bromide  of  ethyl. 

With  the  exception  of  nitrous  oxide  they  all  belong  to  the 
class  of  alcohols  and  ethers,  and  the  substitution-compounds 
having  an  anaesthetic  action  are  probably  almost  indefinite  in 
number.  Even  alcohol  itself  produces  general,  anaesthesia  when 
volatilised  and  inhaled. 

General  Anaesthetics  may  destroy  the  sensibility  of  the 
nerve-centres  indirectly  or  directly.  Anaesthesia  is  induced  in- 
directly by  stopping  the  circulation  in  the  brain  and  thus  arrest- 
ing the  process  of  oxidation  and  tissue-change  in  the  nerve-cells 
which  are  necessary  for  their  functional  activity. 

This  result  may  be  produced  by  draining  the  blood  from  the 
head  into  other  parts  of  the  body.  Thus  in  some  of  the  hospitals 
at  Paris,  before  anaesthetics  were  introduced,  a  plan  was  some- 
times employed  of  rendering  a  patient  insensible  before  an  opera- 
tion, by  laying  him  flat  on  the  ground,  and  then  lifting  him 
very  suddenly  to  a  standing'  posture  by  the  united  efforts  of  six 
or  eight  men  (c/.  pp.  193,  198). 

Local  arrest  of  the  circulation  to  the  brain  by  ligatures  or  by 
compression  of  the  arteries  has  a  similar  effect.  Waller  has 
recommended  diminution  of  the  cerebral  circulation,  by  the 
combined  effects  of  simultaneous  pressure  on  the  carotid  arteries 
and  vagus  nerves,  as  an  easy  means  of  producing  anaesthesia  for 
short  operations. 

Slight  anaesthesia,  usually  accompanied  by  some  giddiness, 
may  be  produced  by  taking  a  number  of  deep  breaths  in  rapid 
succession.  This  may  be  used .  in  order  to  lessen  the  irritability 
of  the  pharynx  in  laryngoscopy  examinations,  and  to  lessen  the 
pain  of  opening  boils  or  abscesses.  The  anaesthesia  thus  pro-, 
duced  may  perhaps  depend  on  anaemia  of  the  brain,  although 
this  is  not  certain. 

Anaesthesia  may  also  be  produced  by  diminishing  the  internal 
respiration  of  the  nerve-cells  through  a  gradually  increasing 
venous  condition  of  the  blood.  Thus  gradual  suffocation  by 
charcoal  fumes  or  carbon  monoxide  causes  complete  insensibility, 
and  the  inhalation  of  nitrogen  and  of  nitrous  oxide  has  a  similar 
action. 

Anaesthesia  may  be  caused  by  the  direct  action  of  drugs  on 
the  nerve-cells  themselves.  Chloroform,  ether,  and  other  allied 
substances  belonging  to  the  alcohol  series  appear  to  act  in  this' 
way.  Although  their  action  is  generally  exerted  through  the 
blood  by  which  they  are  conveyed  to  the  brain  when  inhaled,  yet 


206  PHARMACOLOGY  AND  THERAPEUTICS.       [sect:  i.> 

they  will  also  produce  a  similar  action  if  locally  applied  to  the 
nerve-centres.  Thus  Prevost1  found  that  chloroform  applied 
directly  to  the  brain  of  a  frog  narcotises  it  when  the  aorta  is  tied- 
When  the  aorta  is  again  unligatured,  so  that  the  current  of  blood 
can  again  wash  the  chloroform  away,  the  narcosis  disappears. 
Chloroform  and  ether  when  inhaled  appear  to  act. like  alcohol, 
producing  paralysis  of  the  nerve-centres,  commencing  with  the 
highest  and  proceeding  downwards.  The  rate  of  paralysis,  though 
the  same  in  order,  is  more  rapid  than  that  caused  by  alcohol. 

These  anaesthetics  are,  however,  not  nerve-poisons  only ;  they 
are  protoplasmic  poisons  affecting  simple  organisms,  such  as 
amoebae  and  leucocytes,  and  destroying  also  the  irritability  of 

muscular  fibre. 

This  action  of  anaesthetics  and  especially  that  of  chloroform 
upon  muscular  fibre  is  one  of  considerable  importance  in  reference 
to  the  occasional  stoppage  of  the  heart  and  consequent  death 
during  the  administration  of  anaesthetics. 

The  action  of  anaesthetics  may  be  divided  into  four 
stages : — 

1st.  The  stimulant  stage. 

2nd.  The  narcotic  and  anodyne  stage. 

3rd.  Anaesthetic  stage. 

4th.  Paralytic  stage. 

Stimulant  Stage.— Chloroform  and  ether,  as  already  men- 
tioned, resemble  alcohol  in  their  action,  and,  like  it,  in  small, 
doses  will  produce  a  condition  of  stimulation  and  acceleration  of 
the  circulation  passing  gradually  into  one  of  narcosis,  in  which, 
the  action  of  the  higher  nervous  centres  is  more  or  less  abolished, 
while  that  of  the  lower  centres  still  remains. 

In  small  quantities  chloroform  and  ether  are  sometimes  taken, 
either  internally  or  by  inhalation,  for  their  stimulant  effect.  They 
are  useful  in  lessening  pain  and  spasm,  as  in  neuralgia,  and 
biliary,  renal,  or  intestinal  colic,  when  given  till  the  stimulant  is 
just  passing  into  the  narcotic  stage. 

Narcotic  Stage. — When  pushed  still  further,  sensibility 
becomes  more  impaired,  reflex  action  still  continues,  and  some- 
times, just  as  in  drunkenness,  there  is  a  form  of  wild  delirium 
and  great  excitement.  This  is  much  less  marked  in  feeble  or 
debilitated  persons  than  in  strong  men.  In  the  latter,  the 
struggles  which  occur  in  this  condition  are  sometimes  exceed- 
ingly violent,  the  patient  raising  himself  forcibly  from  the  couch, 
his  muscles  being  in  a  state  of  violent  contraction,  the  face  livid, 
the  veins  turgid,  and  eyeballs  protruding.  Usually  this  condition 
quickly  subsides  and  passes  into  the  third  stage — that  of  complete- 
anaesthesia.  ; 

1  Prevost,  Practitioner  July  1881.  ■ 


cHAP.vii.]    ACTION  OF  DEUGS  ON  THE  BEAIN.  207 

In  order  to  lessen  the  pains  of  labour,  anaesthesia  is  usually 
carried  to  the  commencement  of  the  second  stage. 

Anaesthetic  Stage.— The  third  stage  diners  from  the  second 
in  the  function  of  the  spinal  cord  being  abolished,  as  well  as  those 
of  the  brain ;  ordinary  reflex  is  consequently  abolished,  and  the 
most  common  way  of  ascertaining  whether  this  stage  has  set  in' 
or  not  is  by  drawing  up  the  eyelid  and  touching  the  conjunctiva. 
If  no  reflex  contraction  of  the  eyelid  occurs,  the  anaesthesia  is 
complete.  By  careful  and  judicious  administration  of  the  anaes- 
thetic this  condition  may  be  kept  up  for  a  length  of  time  even 
for  hours,  or  days ;  but  if  the  inhalation  be  carried  too  far,  the 
anaesthetic  passes  into  the  fourth  stage. 

The  third  stage  is  the  one  employed  for  surgical  operations. 

Paralytic  Stage.  —  In  the  fourth  the  respiratory  centre 
becomes  paralysed,  respiration  ceases,  and  the  beats  of  the  heart 
become  feebler  and  may  cease  altogether. 


Uses  of  Anaesthetics. 

Anaesthetics  are  used  not  only  to  lessen  pain  but  to  relax 
muscular  action  and  spasm.  They  are  chiefly  employed  to  lessen 
pain  in  surgical  operations,  in  labour,  and  in  biliary  and  renal  colic. 
They  are  used  to  lessen  muscular  action  and  spasm  in  tetanus, 
in  poisoning  by  strychnine,  in  hydrophobia,  and  in  the  reduction 
of  dislocations,  fractures,  and  hernia.  They  are  also  of  assistance 
in  diagnosis,  by  allowing  careful  examination  to  be  made  of  parts 
which  are  too  tender  or  painful  to  be  examined  without  it,  and 
by  causing  the  phantom  tumours  due  to  spasmodic  contraction 
of  the  muscles  to  disappear. 

Dangers  of  Anaesthetics. — (1)  One  danger  is  that  just  men- 
tioned, of  paralysis  of  the  respiration  from  an  overdose.  This, 
however,  is  one  of  the  least  of  the  dangers,  and  if  the  enfeeble- 
ment  of  the  respiration  be  observed  in  time,  it  is  generally  pos- 
sible to  save  the  patient  by  stopping  inhalation,  and  keeping  up 
artificial  respiration  for  a  little  while  if  necessary. 

(2)  Another  danger  is  from  paralysis  of  the  heart  by  a  too, 
concentrated  chloroform  vapour.  This  is  indicated  by  a  sudden 
stoppage  of  the  heart,  paleness  of  the  face,  and  dilatation  of  the 
pupil  while  the  respiration  may  continue. 

If  this  accident  should  occur,  the  body  of  the  patient  should 
be  inclined  so  that  the  head  should  be  lower  than  the  feet,  and, 
artificial  respiration  should  be  kept  up  briskly  but  regularly,  the 
expiratory  movements  being  made  by  pressure  on  the  thorax  and 
especially  over  the  cardiac  region,  so  that  the  mechanical  pressure; 
should  stimulate  the  heart,  if  possible,  to  renewed  action.  The. 
vapour  of  nitrite  of  amyl  may  also  be  administered  by  holding  a 
piece  of  blotting-paper  or  cloth  on  which  a  few  drops  have  been 
sprinkled  before  the  nose,  while  artificial  respiration  is  kept  up. 


208  PHARMACOLOGY   AND   THERAPEUTICS.       [sect.  t. 

The  inspiratory  movements  may  be  made  by  crawing  the  arms 
backwards  over  the  head,  as  in  Sylvester's  plan. 

(3)  A  third  danger  arises  from  stoppage  of  the  heart  by  a 
combination  of  chloroform-narcosis  and  shock.  This  is  one  of 
the  most  dangerous  conditions.  It  may  occur  even  during  full 
chloroform-narcosis  in  animals  from  operations  on  the  stomach ; 
but  it  is  much  more  common  in  men  from  imperfect  anaesthesia. 
In  very  many  cases  of  so-called  death  from  chloroform  during 
operations,  we  find  it  noted  as  a  matter  of  surprise  that  death 
should  have  occurred  as  the  quantity  of  chloroform  given  was  so 
small.  The  reason  that  death  occurred  probably  was  because 
the  quantity  of  chloroform  given  was  so  small.  Had  the  patient 
been  completely  anaesthetised,  the  risk  would  have  been  very  much 
less.  The  reason  why  imperfect  anaesthesia  is  so  dangerous  is, 
that  chloroform  does  not  paralyse  all  the  reflexes  at  the  same 
time.  A  very  large  proportion  of  the  deaths  from  chloroform 
occur  during  the  extraction  of  teeth,  and  we  may  take  this 
operation  as  a  typical  one  in  regard  to  the  mode  of  action,  both 
of  the  sensory  irritation  and  of  the  chloroform.  When  a  tooth  is 
extracted  in  a  waking  person,  the  irritation  of  the  sensory  nerve 
produced  by  the  operation  has  two  effects  : — 1st,  it  may,  acting 
reflexly  through  the  vagus,  cause  stoppage  of  the  heart  and  a 
consequent  tendency  to  syncope.  2nd,  it  causes  reflex  contrac- 
tion of  the  arterioles,  which  tends  to  raise  the  blood-pressure  and 
counteract  any  tendency  to  syncope  which  the  action  of  the 
vagus  might  have  produced. 

In  complete  anaesthesia  all  these  reflexes  are  paralysed,  and 
thus  irritation  of  the  sensory  nerves  by  the  extraction  of  the 
teeth  has  no  effect  either  upon  the  vagus  or  upon  the  arterioles. 
In  imperfect  anaesthesia,  however,  the  reflex  centre  for  the  arte- 
rioles may  be  paralysed  {ride  p.  204),  while  the  vagus  centre  is 
still  unaffected.  The  irritation  caused  by  the  extraction  of  the 
tooth  may  then  cause  stoppage  of  the  heart,  and  there  being 
nothing  to  counteract  the  tendency  to  faint,  syncope  occurs  and 
may  prove  fatal. 

With  nitrous  oxide  there  is  very  much  less  danger,  inasmuch 
as  the  nitrous  oxide  causes  a  venous  condition  of  the  blood,  with 
consequent  contraction  of  the  arterioles  and  rise  in  the  blood- 
pressure,  so  that  any  tendency  to  syncope  through  vagus-irrita- 
tion is  efficiently  counteracted. 

With  ether,  also,  the  danger  is  very  much  less,  probably  be- 
cause it  has  a  more  equal  effect  on  the  centres  (vide  p.  204) . 

(4)  Another  danger  is  that  of  suffocation  from  blood  passing 
into  the  trachea  in  operations  about  the  mouth  or  nose,  or  from 
the  contents  of  the  stomach  being  drawn  into  the  larynx  when 
vomiting  has  occurred  during  partial  anaesthesia.  In  consequence 
of  this,  it  is  better,  instead  of  giving  chloroform  or  ether  during 
the  whole  of   an   operation  on  the  mouth  or  nose,  to  give  it 


chap,  vni.]    ACTION  OF  DEUGS  ON  THE   BEAIN.  209 

only  at  the  commencement,  and  to  administer  along  with  it,  or 
before  it,  a  hypodermic  injection  of  one-sixth  to  one-third  of  a 
grain  of  morphine.  The  chloroform  anaesthesia  thus  passes  into 
the  morphine  narcosis,  and  the  operation  can  be  finished  without 
pain,  and  without  danger. 

To  prevent  the  occurrence  of  vomiting,  it  is  advisable  not  to 
give  solid  food  for  some  hours  before  an  operation,  though  if 
necessary  a  little  beef-tea  or  stimulant  may  be  given  half  an  hour 
or  so  before  the  administration  of  the  anassthetic. 

Mode  of  administering  Anaesthetics. — In  order  to  obtain 
the  first  stages  of  the  action  of  anaesthetics,  as  in  cases  of  in- 
testinal, biliary,  or  renal  colic,  intense  neuralgia,  or  in  parturition, 
the  best  means  of  administration  is  one  for  the  account  of  which 
I  am  indebted  to  Mr.  W.  J.  Image,  of  Bury  St.  Edmunds.  It 
consists  of  a  tumbler,  at  the  bottom  of  which  is  placed  a  piece  of 
blotting-paper  or  linen  thoroughly  wetted  with  chloroform  or 
ether.  The  patient  holds  the  tumbler  to  the  nose  with  his,  or 
her,  own  hand.  On  account  of  the  form  of  the  tumbler,  sufficient 
air  always  gets  in  at  the  sides,  and  the  patient  cannot  inhale  the 
vapour  in  too  concentrated  a  condition.  As  soon  as  the  anaes- 
thetic begins  to  take  effect,  the  hand  drops,  and  the  inhalation 
ceases.  As  the  effect  again  passes  off,  the  patient  resumes  the 
inhalation.  In  employing  anaesthetics  in  this  way,  however, 
great  care  must  be  taken  that  the  bottle  containing  the  chloro- 
form is  never  entrusted  to  the  patient,  but  is  always  kept  on  a 
table  at  some  little  distance  from  the  bed,  and  that  the  blotting- 
paper  or  lint  in  the  tumbler  is  supplied  with  fresh  chloroform  by 
an  attendant.  If  the  bottle  itself  be  entrusted  to  the  patient, 
as  the  anaesthetic  takes  effect  and  produces  stupidity,  the  stopper 
may  fall  out,  the  whole  contents  of  the  bottle  may  be  sucked  up 
by  the  pillow,  bolster,  bed,  or  bedclothes,  and  the  vapour  being 
inhaled,  fatal  suffocation  may  ensue. 

Another  method  of  administering  chloroform,  which  is  very 
convenient  when  complete  anaesthesia  is  required  for  a  length  of 
time,  and  when  the  supply  of  chloroform  is  limited,  was  devised 
by  Sir  James  Simpson:  it  consists  of  either  a  cup-shaped  in- 
haler, formed  of  a  wire  framework  covered  with  flannel,  or  else 
simply  of  a  single  fold  of  a  pocket-handkerchief  thrown  over  the 
face  :  the  chloroform  is  dropped  upon  the  flannel  or  handkerchief 
just  under  the  nostrils  in  single  drops  at  a  time.  Another  plan 
is  to  pour  some  chloroform  on  to  a  folded  towel  or  pocket-hand- 
kerchief, and  then  place  it  over  the  patient's  face,  taking  care 
that  it  does  not  come  so  close  over  the  nose  as  to  interfere  with  a 
free  admixture  of  air  with  the  chloroform  vapour.  There  is  this 
difference  between  ether  and  chloroform,  that  whereas  it  is  highly 
inadvisable  to  give  chloroform  vapour  in  a  concentrated  condi- 
tion, it  is  requisite  to  give  the  ether  vapour  very  strong,  in  order 
to  produce  an  anaesthetic  effect.     A  combined  administration  of 


210  PHAEMACOLOGY   AND   THEEAPEUTICS.       [sect,  l 

nitrous  oxide  and  ether  is  now  used  to  a  considerable  extent : 
the  nitrous  oxide  producing  rapid  anesthesia,  which  is  kept  up 
by  the  ether. 

Anaesthesia  in  Animals. 

In  the  course  of  many  investigations  into  the  action  of  druga 
on  animals  it  is  necessary  to  perform  experiments  which  would 
be  painful  unless  the  animals  were  anaesthetised.  The  easiest 
way  of  doing  this  with  frogs  or  small  animals,  such  as  mice,  rats, 
or  rabbits,  is  to  put  them  under  a  bell-jar  with  an  opening  at  the 
top.  Into  this  opening  a  piece  of  cotton-wool  or  blotting-paper  is 
put,  and  chloroform  dropped  on  it.  The  vapour  being  heavier 
t;han  air  falls  to  the  bottom,  and  the  animal  soon  becomes  in- 
sensible. The  best  way  of  anaesthetising  cats,  small  dogs,  or  very 
large  rabbits,  is  to  put  them  into  a  wooden  box  or  tin  pail,  and 
stretch  a  towel  tightly  over  the  top.  An  assistant  then  pours 
some  chloroform  on  the  towel  and  anaesthesia  is  quickly  pro- 
duced. Eats  are  most  readily  anaesthetised  by  completely  cover- 
ing the  cage,  in  which  they  are,  with  a  towel,  and  dropping 
chloroform  upon  it. 

Babbits  may  be  very  quickly  anaesthetised  by  the  plan  em- 
ployed by  Pasteur.  It  consists  in  putting  a  piece  of  cloth  or 
blotting-paper  soaked  in  chloroform  round  the  animal's  nose  so 
as  to  exclude  air.  At  once  the  rabbit  ceases  to  breathe,  and  re- 
mains without  breathing  for  about  a  minute.  It  then  begins 
to  struggle,  and  if  the  anaesthetic  be  kept  closely  applied  the 
respiratory  movements  shortly  become  steady  and  regular  and 
the  animal  completely  insensible. 

For  very  large  or  savage  dogs  an  old  packing-case  without  a 
lid  may  be  simply  placed  over  the  animal  and  held  firmly  down, 
or  one  of  the  sides  may  be  furnished  with  hinges  so  as  to  convert 
the  case  into  a  sort  of  kennel.  After  the  dog  is  safely  housed 
large  pieces  of  blotting-paper  or  of  cloth  on  which  chloroform  is 
pourea  are  pushed  through  cracks  in  the  top  of  the  case  or  holes 
specially  made  for  the  purpose.  The  outer  ends  of  the  blotting- 
paper  or  cloth  remaining  outside,  fresh  quantities  of  chloroform 
can  be  introduced  as  required  until  complete  anaesthesia  is  pro- 
duced. Anaesthesia  may  be  maintained  for  almost  any  length  of 
time  that  is  required,  by  putting  a  piece  of  cloth  loosely  round 
the  animal's  nose  and  dropping  chloroform  upon  it.  This  re- 
quires careful  attention,  however,  in  order  to  prevent  danger  from 
an  overdose  on  the  one  hand,  or  partial  recovery  on  the  other. 
I  find  the  most  convenient  way  of  maintaining  the  anaesthesia 
induced  by  chloroform  in  the  way  already  mentioned  is  to  put  a 
cannula  in  the  trachea  and  connect  it  with  a  flask  containing  ether, 
so  that  the  inspired  air  passes  over  the  surface  of  the  ether,  and 
carries  a  quantity  of  the  vapour  with  it  into  the  lungs  of  the 


chap,  viii.]    ACTION  OP  DEUGS  ON  THE  BRAIN.  211 

animal.^  By  means  of  a  peculiar  stopcock,  the  construction  of 
which  is  indicated  in  the  diagram  (Fig.  73),  pure  air  or  air 
loaded  with  ether  vapour  or  a  mixture  of  both  may  be  given. 

The  advantages  of  employing  this  method  and  of  using  ether 
rather  than  chloroform  are  that  complete  anaesthesia  may  be  kept 


Flo.  73. — Diagram  of  a  stopcock  by  which  air  or  vapour,  or  two  kinds  of  gas,  may  be  given 
alone,  or  mixed  together  in  any  proportion. 

up  for  hours  together  with  little  or  no  attention  on  the  part  of 
the  operator,  and  without  the  respiration  or  blood-pressure  being 
seriously  affected  by  the  anaesthetic. 

Another  plan  of  maintaining  anaesthesia  for  a  length  of  time 
is  to  inject  some  laudanum  or  liquid  extract  of  opium  into  a  vein 
after  anaesthesia  has  been  induced  by  chloroform.  Before  the 
effect  of  the  chloroform  has  passed  off,  such  complete  narcosis  is 
produced  by  the  opium  that  no  procedure,  however  painful  it 
might  otherwise  be,  will  produce  the  slightest  evidence  of  sensa- 
tion. "When  the  effect  of  the  anaesthetic  or  of  the  opium  would 
interfere  with  the  investigation  of  the  action  of  a  drug  on  the 
circulation  or  reflex  action,  the  animal  may  be  anaesthetised  by 
chloroform,  and  the  crura  cerebri  divided.  The  channels  by 
which  painful  impressions  are  conveyed  to  the  brain  being  thus 
destroyed  no  pain  can  be  felt,  although  the  reflex  action  of  the  cord 
again  returns  after  the  effects  of  the  chloroform  have  passed  off. 

History  of  the  Discovery  of  Anesthesia. 

This  is  a  subject  of  considerable  interest,  and  has  given  rise 
to  much  discussion.  The  starting-point  of  the  discovery  seems 
to  have  been  Sir  Humphry  Davy's  observations  on  the  pro- 
perties of  nitrous  oxide,  regarding  which  he  said,  '  as  nitrous 
oxide  in  its  extensive  operation  seems  capable  of  destroying 
physical  pain,  it  may  probably  be  used  with  advantage  during 
surgical  operations.'  The  property  of  this  gas  and  also  of  ether 
vapour  to  produce  excitement  when  inhaled,  caused  these  sub- 
stances to  be  used  in  sport,  and  during  their  action  bruises 
were  frequently  received,  but  not  felt.  This  circumstance  excited 
the  attention  of  Dr.  Crawford  W.  Long,  of  Athens,  Georgia,  and, 
in  1842,  he  anaesthetised  a  patient  with  ether  in  order  to  re- 
move a  tumour.  He  was  encouraged  to  do  this  by  the  fact  that 
Dr.  Wilhite,  in  a  frolic,  had  rendered  a  negro  boy  completely 
insensible  without  any  bad  results.     Mr.  Horace  Wells,  without 

p  2 


212  PHARMACOLOGY  AND   THEEAPEUTICS.       [sect.  i. 

knowing  what  Dr.  Long  had  done,  used  nitrous  oxide  as  an 
anesthetic  in  1844.  His  pupil,  Mr.  Morton,  wishing  to  use  it 
also,  asked  him  how  to  make  it,  and  was  referred  to  a  scientific 
chemist,  Dr.  Jackson.  Jackson  advised  Morton  to  use  sulphuric 
ether,  a's  it  had  similar  properties  to  nitrous  oxide  and  was  easier 
to  get.  Acting  on  this  suggestion  Morton  used  ether  in  dentistry, 
and  induced  Drs.  Warren,  Haywood,  and  Bigelow  to  perform 
important  surgical  operations  on  patients  whom  he  anaesthetised 
by  it.  From  this  time  onwards  anaesthesia  has  been  regularly 
used  in  medical  operations.  Shortly  afterwards,  Sir  J.  Y.  Simp- 
son discovered  the  use  of  chloroform  as  an  anaesthetic,  and  it  has 
been  chiefly  employed  in  Great  Britain,  but  in  America  ether  has 
always  retained  its  original  place. 

Antispasmodics. 

These  are  remedies  which  prevent  or  relieve  spasm. 

Spasm  is  contraction  of  voluntary  or  involuntary  muscles, 
in  a  way  that  is  unnecessary  or  injurious  to  the  organism 
generally.  The  spasmodic  contraction  of  muscles  may  sometimes 
be  excessive  in  degree,  as  in  the  calves  of  the  legs  in  cramp,  or 
in  the  fibres  of  the  intestinal  walls  in  colic.  Sometimes  it  is  not 
excessive  in  degree,  but  are  merely  out  of  place,  as,  for  example, 
in  the  slight  twitchings  of  the  face  or  fingers  which  occur  in  mild 
cases  of  chorea. 

Spasm  may  affect  single  muscles,  or  it  may  affect  groups  of 
muscles  and  the  nerve-centres  by  which  they  are  set  in  action  5 
these  centres  may  sometimes  be  very  limited  in  extent,  but  some- 
times a  great  number,  or  indeed  most  of  the  motor  centres  in 
the  body,  may  be  involved,  as  in  the  convulsions  of  hysteria. 
Spasm  is,  indeed,  a  kind  of  insubordination  in  which  the 
individual  muscles  or  nerve-centres  act  for  themselves  without 
reference  to  those  higher  centres  which  ought  to  co-ordinate  their 
action  for  the  general  good  of  the  organism.  It  may  be  due,  there- 
fore, either  to  excess  of  action  in  the  muscles  or  local  centres,  or 
diminished  power  of  the  higher  co-ordinating  centres.  As  a  rule 
it  is  due  to  diminished  action  of  the  co-ordinating  or  inhibitory 
centres,  rather  than  to  excess  of  action  in  the  motor  centres ;  it  is, 
therefore,  a  disease  rather  of  debility  and  deficient  co-ordination 
than  of  excessive  strength. 

Cramps  in  the  muscles  may  come  on  from  their  exhaustion  by 
excessive  exertion,  the  waste  products  of  their  functional  activity 
appearing  to  act  as  local  irritants.  This  is  relieved  by  the  removal 
of  these  waste  products ;  as,  for  example,  by  shampooing.  In  the 
intestine,  cramp  may  be  due  to  the  presence  of  a  local  irritant, 
which  ought'  in  the  normal  condition  to  produce  increased 
peristalsis,  and  thus  ensure  the  speedy  removal  of  the  offending 
substance.    From  some  abnormal  condition  the  muscular  fibres 


chap,  vin.]    ACTION  OF  DRUGS  ON  THE  BRAIN.  213 

around  the  irritant  contract  excessively,  and  do  not  pass  on  the 
stimulus  to  those  adjoining.  Prom  this  want  of  co-ordination 
painful  and  useless  spasm  occurs.  In  order  to  remove  it  we  apply 
warmth  to  the  abdomen  so  as  to  increase  the  functional  activity, 
both  of  the  muscular  fibres  and  of  the  ganglia  of  the  intestine 
(pp.  138,  140).  Peristalsis  then  occurring  instead  of  cramp,  the 
pain  disappears,  and  the  offending  body  is  passed  onwards  and 
removed.  Or  we  give  internally  aromatic  oils,  which  will  have  a 
tendency  to  increase  the  regular  peristalsis ;  or  yet  again,  we 
may  give  opium  for  the  purpose  of  lessening  the  sensibility  of 
the  irritated  part,  or  the  nerves  connected  with  it,  and  thus  again 
bringing  it  into  relationship  with  other  parts  of  the  body. 
General  antispasmodics  may  act  either 

(1)  By  increasing  the  power  of  the  higher  nervous  centres 
to  keep  the  lower  ones  and  the  muscles  in  proper  subordina- 
tion, or — 

(2)  By  lessening  the  activity  of  over-excited  muscles  or  lower 
nervous  centres. 

On  this  account  we  find  stimulants  and  antispasmodics  very 
much  classed  together.  Those  drugs  which  stimulate  the 
circulation  and  increase  the  nutrition  of  the  higher  nerve-centres 
and  the  co-ordinating  power,  tend  to  prevent  spasm.  Thus, 
small  quantities  of  alcohol  and  ether,  by  acting  in  this  way,  tend 
to  prevent  general  spasm,  as  in  hysteria,  nervous  agitation,  or 
trembling,  or  remove  local  spasm,  as  in  colic. 

Camphor,  which  is  frequently  used  as  an  antispasmodic,  has 
a  stimulant  action  on  the  brain,  spinal  cord,  circulation,  and 
respiration.  It  is  probable  that  such  antispasmodic  powers  as 
it  possesses  are  due  to  its  exciting  the  higher  centres,  and  in- 
creasing their  inhibitory  powers  over  the  lower  (p.  214).  Bromo- 
camphor  has  a  somewhat  similar  action. 

Valerian,  asafoetida,  musk,  castor,  and  other  aromatic  sub- 
stances, have  an  antispasmodic  action  which  we  do  not  under- 
stand. It  is  possible  that  they  affect  some  part  of  the  brain 
particularly,  so  as  to  increase  its  regulating  power,  in  much  the 
same  way  as  camphor. 

Other  antispasmodics,  such  as  bromide  of  potassium,  lessen 
the  irritability  of  motor  centres.  Borneol  and  menthol  have  a 
depressing  and  finally  paralysing  effect  upon  motor,  sensory,  and 
reflex  centres  in  the  brain  and  spinal  cord.  In  this  respect  they 
differ  greatly  from  ordinary  camphor,  which  has  an  exciting 
action  upon  these  structures,  though  they  may  perhaps  be  still 
more  useful  as  antispasmodics. 

Other  antispasmodics,  instead  of  lessening  the  irritability  of 
nerve-centres,  may  paralyse  the  structures  through  which  the 
nerves  act.  Thus,  nitrite  of  amyl  appears  to  arrest  the  spasm  of 
the  vessels  in  angina  pectoris,  by  causing  paralysis  of  the  vessels 
themselves  or  of  the  peripheral  ends  of  the  vaso-motor  nerves. 


214 


PHAEMACOLOGY  AND   THEEAPEUTICS.       [sect.  t. 


Adjuvants. — As  spasm  is  usually  an  indication  of  deficient 
nervous  power,  tonics,  as  quinine,  iron,  cod-liver  oil,  arsenic, 
sulphur,  cold  baths,  and  moderate  exercise,  are  useful  as  adju- 
vants. 

It  has  already  been  mentioned,  that  a  healthy  condition  of 
the  various  parts  of  the  body  depends  on  proper  nutrition  and 
proper  removal  of  waste.  Therefore,  when  there  is  a  tendency 
to  spasm,  the  diet  should  be  plain,  but  nutritious.  Those  condi- 
tions which  tend  to  cause  excessive  waste  should  be  avoided,  such 
as  exciting  emotions,  excessive  bodily  or  mental  work,  a  close 
atmosphere,  and  late  hours.  Attention  must  be  paid  also  to  the 
proper  removal  of  all  waste,  by  the  use  of  purgatives,  cholagogues, 
or  diuretics  if  necessary. 

Great  irritability  of  the  nervous  system  is  usually  observed 
in  gouty  subjects  before  an  attack  of  gout  comes  on.  It  is  uncer- 
tain to  what  this  irritability  is  due,  but  it  may  not  improbably  be 
caused  by  the  retention  within  the  body  of  the  products  of  tissue- 
waste.  Some  years  ago  there  was  considerable  discussion  regard- 
ing the  active  ingredient  of  bromide  of  potassium,  some  attribut- 
ing its  antispasmodic  action  to  the  bromine,  and  others  to  the 
potassium.  It  occurred  to  me  that  possibly  its  action  might  be 
partly  due  simply  to  its  action  as  a  saline  leading  the  patient 
to  drink  more  water,  and  thus  assisting  the  elimination  of  the 
products  of  tissue-waste.  I  accordingly  tried  30-grain  doses  of 
chloride  of  sodium  in  cases  of  epilepsy.  In  some  it  did  little  or 
no  good,  but  in  a  few  it  appeared  to  have  nearly  as  powerful  an 
action  as  bromide  of  potassium. 

Uses. — Antispasmodics  are  used  in  convulsive  diseases. 

The  antispasmodics  used  in  hysteria  may  be  divided  into 
substances  which  exert  on  the  higher  nerve-centres  a  sedative, 
tonic,  or  stimulant  action,  thus  : 


I.  Sedatives 


.   Alkaline  bromides. 
Zinc  salts. 


Castor      . 

Sumbul    . 
►  Valerian  . 

Asafoetida 
Ammoniac  um 
Galbanum 


Derived  from  the  genital  organs  of 

animals. 
Similar  in  the  nature  of  their  odour 

to  the  above,  though  derived  from 

plants. 

I  Containing  sulphur  oils. 


II.  Tonics 
III.  Stimulants, 
whichhaveapower-\  Musk 
ful  odour,  and  pro- 
bably  act    on    the 
higher  centres 

through  the  olfac- 
tory organs,  either 
by  direct  applica- 
tion or  during  their^ 
elimination  (p.  41). 

In  epilepsy,  laryngismus  stridulus,  and  infantile  convulsions, 
bromides  of  potassium,  sodium,  ammonium,  and  calcium,  nitrite 
of  sodium,  salts  of  silver,  zinc,  and  copper. 

In  chorea,  arsenic,  conium,  the  salts  of  copper  and  zinc. 

In  spasmodic  asthma,  lobelia,  stramonium. 

In  spasm  of  the  blood-vessels,  nitrite  of  amyl  and  other 
itrites. 


chap,  viii.]    ACTION  OP  DKUGS  ON  THE  BEAIN.  215 


Action  of  Drugs  on  the  Cerebellum. 

The  chief  function  of  the  cerebellum  appears  to  be  the  main- 
tenance of  equilibrium.  Symmetrical  lesions  on  both  sides  of  the 
organ  or  division  of  it  down  the  centre  from  before  backwards, 
cause  very  little  disturbance  of  the  equilibrium,  but  when  a  lesion 
is  unsymmetrical  the  equilibrium  is  disordered. 

According  to  Ferrier,  if  the  lesion  affects  the  whole  of  a  lateral 
lobe,  there  is  a  tendency  for  the  animal  to  roll  over  towards  the 
affected  side.  In  an  animal  standing  on  all  fours  or  lying  on  the 
ground,  we  regard  the  centre  of  the  back  as  the  point  of  move- 
ment, but  in  a  man  standing  upright  we  usually  take  the  face,  and 
therefore  what  we  should  regard  in  an  animal  as  rolling  towards 
the  affected  side,  would  be  equivalent  hi  man  to  a  rotation 
towards  the  sound  side.  If  the  lesion  is  limited  to  one  part  of 
the  lateral  lobe,  it  may  not  cause  rotation,  but  only  falling  to- 
wards the  opposite  side.  When  the  anterior  part  of  the  middle 
lobe  of  the  cerebellum  is  injured,  the  animal  tends  to  fall  forward, 
and  in  walking  usually  stumbles,  or  falls  on  its  face.  When  the 
posterior  part  of  the  middle  lobe  of  the  cerebellum  is  injured,  the 
head  is  drawn  backwards  and  there  is  a  continual  tendency  to 
fall  backwards  when  moving.' 

Injuries  of  the  cerebellum  are  frequently  associated  with  a 
certain  amount  of  nystagmus,  and  in  all  probability  the  com- 
plete or  partial  inability  to  walk  or  stand  which  alcohol  produces, 
is  due  to  its  action  on  the  cerebellum. 

Different  kinds  of  spirit  appear  to  have  a  tendency  to  affect 
different  parts  of  the  cerebellum,  for  good  wine  or  beer  is  said  to 
make  a  man  fall  on  his  side,  whisky,  and  especially  Irish  whisky, 
on  his  face,  and  cider  or  perry  on  his  back.2  These  disturbances 
of  the  equilibrium  correspond  exactly  with  those  caused  by  injury 
to  the  lateral  lobes,  and  to  the  anterior  and  posterior  part  of  the 
middle  lobe  of  the  cerebellum  respectively.  Apomorphine  in 
large  doses  appears  also  to  have  an  action  on  the  cerebellum  or 
corpora  quadrigemina,  as  the  animal  poisoned  by  it  does  not 
vomit,  but  moves  round  and  round  in  a  circle. 

The  action  of  alcohol  on  frogs  is  peculiar  and  differs  from 
that  of  other  narcotics,  inasmuch  as  it  appears  to  affect  unequally 
the  two  sides  of  the  nervous  apparatus  by  which  the  equilibrium 
is  maintained,  so  that  in  a  certain  stage  of  alcohol-poisoning 
they  excite  similar  manege  movements  to  those  which  occur  after 
division  of  the  corpora  quadrigemina  on  one  side.3 

1  Ferrier,  Functions  of  the  Brain,  p.  94. 

2  Shorthouse,  Baily's  Magazine  of  Sports,  1880,  vol.  xxxv.  p.  396. 

s  Wilhelm  Wundt :   Untersuchungen  zur  Mechanik  der  Nerven  und  Nerven- 
centren.     Zweite  Abtheilung,  1876.     Stuttgart. 


216  PHAKMACOLOGY  AND  THEKAPEUTICS.     {sect. 


CHAPTEE  IX. 

ACTION  OF  DBUGS  ON  THE  OEGANS  OF  SPECIAL  SENSE. 

Action  of  Drugs  on  the  Eye. 

Action  on  the  Conjunctiva.  —  Before  light  can  reach  the 
retina,  it  has  to  pass  through  the  cornea,  which  is  covered  by 
epithelium  continuous  with  that  of  the  conjunctiva.  Alterations 
in  either  or  both  of  these  textures  are  therefore  very  important 
in  regard  to  the  integrity  of  vision.  The  chief  drugs  employed  in 
the  local  treatment  of  diseases  of  the  cornea  and  conjunctiva  are 
warmth,  moist  and  dry,  anaesthetics,  anodynes,  antiphlogistics, 
antiseptics,  and  astringents.  The  chief  astringents  are  per- 
chloride  of  mercury,  oxide  of  mercury,  and  nitrate  of  silver.  The 
chief  antiseptics  are  perehloride  of  mercury,  quinine,  boric  acid,  • 
and  sulphocarbolate  of  sodium.  The  chief  sedatives  are  hydro- 
cyanic acid,  opium,  belladonna,  atropine,  and  cocaine.  There 
are  two  astringents  in  common  use  which  ought  to  be  avoided, 
these  are  solutions  of  lead  and  of  alum.  Lead  salts  are  objection- 
able, because  if  there  is  any  ulceration  on  the  cornea  they  may 
form  an  insoluble  albuminate  and  cause  permanent  opacity. 
Salts  of  alum  are  said  by  Tweedy  to  be  perhaps  still  more  objec- 
tionable, because  alum  has  the  power  of  dissolving  the  cement  by 
which  the  fibrillae  of  the  cornea  are  held  together,  and  this  is 
very  apt  to  give  rise  to  perforation  of  the  cornea  whenever  the 
epithelium  is  removed  by  injury  or  inflammation.  Tweedy  also 
thinks  that  strong  solutions  of  common  salt,  ten  per  cent,  or 
more,  and  solution  of  permanganate  of  potassium  also  dissolve 
the  corneal  cement  and  should  therefore  be  avoided  in  inflamma- 
tion of  the  conjunctiva  or  of  the  cornea.  He  considers  that  sul- 
phate of  zinc  should  be  avoided,  for  the  same  reason,  but  it  is 
largely  used  by  others.  The  best  astringent  is  probably  perehloride 
of  mercury,  -Jjth  to  -J^-th  of  a  grain  to  an  ounce  of  water,  and 
coloured  with  cochineal.  The  next  best  is  an  aqueous  solution 
of  boric  acid,  containing  3  to  8  grains  of  it  with  3  to  10  grains  of 
sulphocarbolate  of  sodium  per  ounce. 

The  chief  effects  which  drugs  produce  on  the  eye,  besides 
those  just  described,  are  alterations  in  the  size  of  the  pupil,  in 


chap,  ix.}    ACTION  OF  DEUGS  ON  SPECIAL  SENSE.         217 

the  power  of  accommodation,  in  the  intra-ocular  pressure,  in  the 
sensitiveness  of  the  retina  to  impressions,  and  in  the  apparent 
colour  of  objects. 

Action  of  Drugs  on  the  Lacrimal  Secretion.— The  great 
power  of  certain  volatile  oils,  such  as  those  of  onion  or  mustard, 
to  irritate  the  eyes  and  cause  secretion  of  tears  is  well  known. 
The  prolonged  action  of  atropine  diminishes  the  secretion.  Ese- 
rine  abolishes  the  action  of  atropine,  and  quickly  increases  the 
secretion.1 

Projection  of  the  Eyeball.— The  non-striated  muscular  fibres 
which  are  contained  in  the  orbital  membrane  and  in  both  eyelids 
push  the  eyeball  forward  and  draw  the  eyelids  back  when  they 
contract.  Like  the  dilator  pupillae  they  are  innervated  by  the 
sympathetic,  and  consequently  some  degree  of  protrusion  of  the 
eyeball  is  frequently  produced  by  such  substances  as  dilate  the 
pupil,  and  especially  by  cocaine.  Excessive  pain,  or  an  asphyxial 
condition  of  the  blood,  has  a  powerful  action  in  producing  this 
effect,  so  that  in  men  subjected  to  torture  in  the  Middle  Ages  pro- 
trusion of  the  eyeballs  was  noticed;  and  both  in  animals  and  men 
dying  from  rapid  asphyxia  the  eyeballs  may  seem  as  if  starting 
from  the  head. 

Action  on  the  Pupil. — The  iris  is  usually  said  to  consist  of 
two  muscles,  the  sphincter,  which  has  circular  fibres  and  contracts 
the  pupil,  and  the  dilator,  which  has  radial  fibres  and  dilates  the 
■  pupil.  All  observers  are  agreed  regarding  the  sphincter  muscle 
of  the  eyes,  but  some  deny  the  existence  of  the  dilator  muscle; 
In  the  following  description,  however,  I  shall  take  the  view  which 
is  usually  accepted.2 

The  sphincter  receives  its  motor  nervous  supply  from  the 
third  nerve,  and  the  dilator  from  the  cervical  sympathetic.  The 
nervous  centre  for  the  contraction  of  the  pupil  probably  lies  in 
the  corpora  quadrigemina ;  the  nerve-centre  for  the  dilatation 
of  the  pupil  lies  in  the  medulla  oblongata,  but  there  seems  to 
be  another  dilating  centre,  situated  in  the  floor  of  the  front  part  of 
the  aqueduct  of  Sylvius.3  The  contracting  -nerves  are  contained 
in  the  third  nerve,  and  pass  to  the  ciliary  ganglion,  and  thence 
to  the,  eye.  Along  with  them  motor  fibres  pass  also  to  the  ciliary 
muscle.  This  muscle  when  contracted  lessens  the  tension  of  the 
suspensory  ligament  on  the  lens,  allowing  the  latter  to  become 


1  Maynard,  Vmshoto's  Archiv,  vol.  lxxxix.  p.  258. 

2  At  present  it  is  generally  assumed  that  muscular  fibres,  either  voluntary  or 
involuntary,  contract  only  in  the  direction  of  their  length.  If  we  suppose  that  they 
can  contract  either  in  the  direction  of  their  length  or  their  width,  the  movements 
of  the  iris  might  be  more  readily  explained.  At  present  we  assume  the  presence 
of  a  dilator  muscle,  which  is  almost  certainly  absent  in  many  animals,  in  order  to 
explain  phenomena  which  might  be  explained  just  as  readily  by  the  supposition  that 
the  muscular  fibres  which  are  present  can  contract  in  two  directions  {see  p.  117). 

•  Foster's  Physiology,  4th  ed. 


318  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect,  i, 

more  spherical,  and  thus  accommodating  the  eye  for  near  objects, 
Such  accommodation  and  contraction  of  the  pupil  generally  ac- 
company one  another.  The  arrangement  of  the  nerves  of  the  eye 
is  very  diagrammatically  shown  in  Fig.  74.  A  few  of  the  dilating 
fibres  are  contained  in  the  fifth  nerve,  but  most  of  them  pass 
down  the  spinal  cord  to  the  cilio-spinal  region  in  the  lower  cervical 
and  upper  dorsal  part  of  the  cord,  and  thence  through  the  second 
dorsal  nerve  in  monkeys  and  probably  in  man,  or  through  the 
inferior  cervical  and  superior  dorsal  nerves  in  the  rabbit,  into 
the  cervical  sympathetic,  in  which  they  again  ascend  to  the  eye. 


Ciliary  ganglion  

Muscle  for  accommodation 

Lens 

Sphincter  iridis    

Dilator  pupil  he 

Vesselsofeye   


Nucleus  of  third  nerve. 
Central  origin  of  sympathetic. 

Sympathetic  centre  in  medulla. 
Sympathetic  fibres. 


IjlQ.  *  4.— uiagram  to  show  the  nervous  supply  of  the  eye.  a,  nerves  to  the  ciliary  muscle  regu- 
lating accommodation  ;  6,  nerves  to  the  contracting  fibres,  and  c,  nerves  to  the  dilating  fibres  of 
the  iris ;  d,  vaso-motor  nerves  to  the  vessels  of  the  eye.  The  iris  is  put  apparently  behind 
instead  of  in  front  of  the  lens  for  convenience  in  showing  the  passage  of  nerves  to  it. 


Along  with  the  dilating  fibres  others  pass  to  supply  the  orbital 
muscle  at  the  back  of  the  orbit,  which  causes  protrusion  of  the 
eyeball,  as  already  mentioned.  There  are  also  other  fibres  from 
the  sympathetic  (vaso-motor)  which  supply  the  muscular  coats 
of  the  arteries  of  the  ciliary  vessels. 

The  dilating  centre  may  be  stimulated  directly  by  venous 
blood  circulating  in  it.  In  consequence  of  this  the  pupils  usually 
dilate  much  when  the  respiration  is  imperfect,  as  during  dyspnoea; 
but  when  the  asphyxia  becomes  complete  the  centre  again  be- 
comes paralysed  and  the  size  of  the  pupil  diminishes.  It  may  be 
stimulated  reflexly  by  irritation  of  sensory  nerves,  so  that  dilata- 
tion of  the  pupil  has  been  used  as  an  indication  of  sensation  in 
animals  paralysed  by  curare.  It  seems  to  be  readily  stimulated 
by  irritation  of  the  genital  organs.  This  is  probably  the  reason 
why  dilatation  of  the  pupil  frequently  occurs  in  persons  suffering 
from  irritation  of  the  genital  organs.  It  is  probably  also  readily 
stimulated  by  irritation  of  the  intestinal  canal,  and  such  irritation 
may  be  the  cause  of  dilatation  of  the  pupil  in  children  suffering 
from  worms,  and  in  cases  of  poisoning  by  drugs  which  irritate 
the  gastro-intestinal  canal,  like  aconite. 

The  drugs  which  act  upon  the  iris  are  divided  into  two  classes : 
Mydriatics  which  dilate,  and  Myotics  which  contract  the  pupil. 
The  most  important  of  these  are  such  drugs  as  have  a  local  action 


chap,  ix.]    ACTION  OF  DEUGS  ON  SPECIAL  SENSE.         219 

on  the  eye,  and  they  alone  are  used  in  ophthalmic  medicine.   They 
are  indicated  in  the  following  list  by  an  *. 

Mydriatics.  Myotics. 

General  anesthetics —  General  anesthetics— 
chloroform,  ether,  &c.  chloroform,  ether,  &c. 

*Atropine.  *Calabar  bean. 
*Belladonna. 

Belladonnine. 

Benzoyltropine. 

Cocaine. 

Daturine. 
*Duboisine. 

Gelsemine  locally.  Gelsemine  internally. 

*Homatropine  (oxytoluylic-  Jaborandi. 

acid-tropine).  Lobeline  internally. 

Hyoscyamine.  Morphine  internally. 

Muscarine  locally  (?).  Muscarine  internally. 

„         locally. 

Narcissine.  Nicotine  locally. 

Piturine.  Opium. 

Scopalein.  *Physostigmine  (eserine). 

Stramonium.  Pilocarpine. 

Thebaine. 

Ansesthetics  occur  in  both  classes,  because  they  cause  con- 
traction towards  the  commencement  of  their  action,  while  later 
on  they  cause  dilatation.  The  probable  reason  of  this  is  that  at 
first  they  lessen  reflex  action,  so  that  the  reflex  dilatation  of  the 
pupil  by  stimulation  of  sensory  nerves  is  abolished.  Later  on, 
when  they  begin  to  paralyse  the  respiration,  the  accumulation  of 
venous  blood  causes  irritation  of  the  dilating  centre  and  widens 
the  pupil.  Dilatation  of  the  pupil  during  the  administration  of 
ansesthetics  is  therefore  to  be  regarded  as  a  sign  of  imperfect 
aeration  of  the  blood,  due  either  to  embarrassed  or  failing 
respiration  (p.  218)  or  failing  circulation  (p.  207). 

The  contraction  caused  by  morphine  is  also  central,  and  pro- 
bably due  to  a  similar  cause. 

It  is  possible  that  the  local  application  of  drugs  to  the  eyes 
may  have  an  action  on  the  pupil  due  merely  to  their  effect  as 
irritants,  and  independent  of  any  special  action  on  the  iris,  for 
E.  H.  Weber  '  found  that  local  irritation  at  the  margin  of  the 
cornea  causes  partial  dilatation.  Irritation  in  the  middle  of  the 
cornea  causes  rather  contraction  of  the  pupil.  Localised  irrita- 
tion at  the  margin  of  the  iris  may  cause  dilatation  at  that  part. 

The  reason  why  muscarine  has  been  found  by  Binger  and 

1  Quoted  by  Landois.  Physiologic,  1880,  p.  799. 


220  PHAKMACOLOGY  AND   THERAPEUTICS,      [sect.  i. 

Morshead  to  dilate  the  pupil  when  applied  locally  is  probably  that 
the  solution  they  used  was  very  irritating,  either  from  its  strength 
or  for  some  other  reason,  while  Schmiedeberg  and  Harnack  found 
it  to  contract  the  pupil  both  when  given  internally  and  applied 
locally. 

The  contraction  of  the  pupil  noticed  by  Eossbach  in  rabbits 
immediately  after  the  application  of  atropine,  may  also  have  been 
due  to  local  irritation.  The  occurrence  of  dilatation  in  one  case 
and  of  contraction  in  the  other  may  possibly  have  been  due  to  the 
solution  being  dropped  into  the  eye  in  a  different  way  in  the  two 
cases. 

The  commonest  and  most  important  local  mydriatic  and 
myotic  are  respectively  atropine  and  physostigmine  (eserine). 

From  ten  to  twenty  minutes  after  a  solution  of  atropine  has 
been  dropped  on  the  eye,  the  pupil  dilates  and  the  ciliary  muscle 
becomes  paralysed,  so  that  the  accommodation  for  near  objects  is 
no  longer  possible,  and  the  eye  remains  focussed  for  distant  ob- 
jects. When  a  solution  of  physostigmine  is  dropped  into  the  eye, 
the  pupil  contracts  and  the  ciliary  muscle  becomes  spasmodically 
contracted,  so  that  the  eye  is  accommodated  for  near  objects. 

It  is  very  difficult  to  explain  the  mode  of  action  of  these 
drugs  satisfactorily,  and  authorities  are  by  no  means  agreed 
regarding  it.  That  the  action  is  local  is  shown  by  the  fact  that 
when  either  atropine  or  physostigmine  is  applied  to  one  eye  its 
action  is  limited  to  it  and  the  other  remains  unaffected.  If  care 
be  taken  to  limit  the  application  of  a  solution  of  atropine  to  one 
side  of  the  margin  of  the  cornea,  local  dilatation  of  the  corre- 
sponding part  of  the  pupil  may  be  produced. 

Dilatation  of  the  pupil  may  be  due  to 

(1)  Paralysis  of  the  sphincter,  or 

(2)  Excessive  action  of  the  dilator,  or 

(3)  Both  conditions  combined. 

Paralysis  of  the  sphincter  may  be  due  to  (a)  imperfect  action 
or  paralysis  of  the  oculo-motor  centre  in  the  corpora  quadri- 
gemina,  (b)  to  paralysis  of  the  ends  of  the  third  nerve  in  the 
sphincter  iridis,  or  (c)  to  the  action  of  the  drug  upon  the  mus- 
cular fibres  of  the  sphincter  itself,  or  to  a  combination  of  two  or 
more  of  these  factors. 

Along  with  the  factors  just  mentioned  might  be  associated 
excessive  contraction  of  the  dilator  muscle,  which  may  be  due  to 
stimulation  (1)  of  the  sympathetic  centre  in  the  medulla,  (2)  of  the 
ends  of  the  sympathetic  in  the  dilator  muscle,  or  (3)  of  the  dilator 
muscle  itself. 

Excluding  for  the  present  the  question  of  excessive  action  of  the 
dilator  muscle  and  confining  ourselves  to  the  causes  of  paralysis, 
we  see  that  paralysis  of  the  cerebral  oculo-motor  centre  as  a 
factor  in  dilatation  of  the  pupil  by  atropine  is  excluded  by  the 
local  action  of  the  drug,  by  the  experiments .  of  Bernard  and 


chap,  ix.]    ACTION  OF  DEUGS  ON  SPECIAL  SENSE.         221 

others,  which  show  that  dilatation  occurs  from  the  local  action  of 
atropine  when  the  ciliary  ganglion  is  extirpated  and  all  the  nerves 
of  the  eye  have  been  divided,  and  by  the  mydriatic  action  of  atro- 
pine even  in  the  exsected  eye.  We  can  now  limit  its  action  either 
to  paralysis  of  the  ends  of  the  oculo-motor  nerve,  or  paralysis 
of  the  muscular  fibres  of  the  sphincter. 

That  the  ends  of  the  oculo-motor  nerve  in  the  sphincter  iridis 
are  paralysed  is  shown  by  the  experiment  that  when  the  pupil  is 
under  the  full  action  of  atropine,  irritation  of  the  third  nerve  will 
not  produce  a*ny  contraction  in  it,  although  the  sphincter  will  still 
contract  when  stimulated  directly. 

Here  also  we  find  the  same  relation  between  the  action  of 
atropine  on  nerves  supplying  striated  and  non-striated  muscle 
that  we  have  already  noticed  in  the  case  of  the  oesophagus  (p.  139), 
for  in  most  animals  the  iris  consists  of  unstriated  muscular  fibre, 
and  atropine  causes  dilatation  ;  but  in  birds  the  iris  consists  of 
striated  muscular  fibre,  and  atropine  causes  no  dilatation.  Para- 
lysis of  the  ends  of  the  oculo-motor  nerve  in  the  iris  itself  may  be 
looked  upon  as  one  of  the  factors  in  dilatation  by  atropine,  and 
similar  paralysis  of  the  fibres  supplying  the  ciliary  musele  may 
be  regarded  as  the  cause  of  loss  of  accommodation. 

In  addition  to  this,  however,  when  the  dose  of  atropine  is 
large,  the  muscular  fibres  of  the  sphincter  themselves  become 
paralysed,  and  fail  to  contract  even  when  directly  irritated. 

The  question  now  arises  whether  in  addition  to  paralysis  of 
the  oculo-motor  nerve  there  is  not  also  excessive  action  of  the 
dilator  muscle.  That  such  action  of  the  dilator  is  actually  pre- 
sent appears  to  be  shown  by  the  following  fact,  viz.  that  the 
dilatation  caused  by  atropine  does  not  appear  to  be  merely  pas- 
sive, but  occurs  with  such  force  as  to  tear  the  iris  away  from  the 
lens,  and  break  down  inflammatory  adhesions  which  may  have 
formed  between  them.  This  conclusion  has  been  considered  to 
be  supported  also  by  the  facts  : — (a)  That  when  the  oculo-motor 
nerve  is  divided  the  pupil  does  not  dilate  nearly  to  the  same 
extent  as  it  does  from  the  application  of  atropine.  This  is  shown 
both  by  a.  comparison  of  measurements  of  the  eye  under  the  two 
conditions  and  by  the  observation  that  after  the  nerves  have  been 
divided  and  partial  dilatation  produced,  atropine  causes  the  pupil 
to  dilate  still  more.  And  similarly  in  dilatation  due  to  paralysis 
atropine  increases  the  mydriasis.  (6)  When  the  pupil  is  dilated 
by  atropine,  section  of  the  sympathetic  in  the  neck  lessens  the 
dilatation. 

We  may  consider,  then,  with  tolerable  certainty,  that  dilata- 
tion caused  by  atropine  is  due  to  increased  action  of  the  dilator 
as  well  as  diminished  action  of  the  sphincter  muscles  of  the  iris. 

Contraction  of  the  pupil  may  be  due  to 

(1)  Excessive  action  of  the  sphincter,  or 

(2)  Paralysis  of  the  dilator. 


222  PHAEMACOLOGY  AND   THEEAPEUTICS.      [sect.  i. 

That  the  contraction  caused  by  physostigmine  is  not  due  to 
paralysis  of  the  dilator  is  shown  by  the  pupil  dilating  somewhat 
when  shaded,  even  when  the  drug  is  exerting  a  well-marked 
action.  Excessive  action  of  the  sphincter  must  therefore  be  re- 
garded as  the  cause  of  the  myosis.  Such  action  may  be  due  to 
stimulation  (1)  of  the  oculo-motor  cerebral  centre,  (2)  of  the  ends 
of  the  oculo-motor  nerve  in  the  sphincter,  or  (3)  to  increased 
action  of  the  muscular  fibres  in  the  sphincter  from  the  direct 
effect  of  the  drug  upon  them.  The  local  action  of  physostigmine 
upon  the  eye  excludes  the  cerebral  centre,  and  leaves  for  our  con- 
sideration stimulation  of  the  ends  of  the  nerves  and  of  the  mus- 
cular fibres  themselves. 

These  two  structures  seem  to  be  specially  affected  by  differ- 
ent drugs— so  that  local  myotics  may  be  divided  into  two 
classes — 

1st.  Those  which  act  upon  the  peripheral  ends  of  the  oculo- 
motor nerve. 

2nd.  Those  which  affect  the  muscular  fibre  of  the  sphincter 
iridis. 

The  first  class  includes  muscarine,  pilocarpine,'  and  nicotine, 
wbereas  physostigmine  belongs  to  the  second. 

Muscarine,  pilocarpine,  and  nicotine,  when  applied  to  the 
eye,  cause  contraction  of  the  pupil  and  spasm  of  accommodation. 
Atropine,  as  we  have  already  seen,  not  only  paralyses  the  ends 
of  the  oculo-motor  nerve,  which  these  drugs  stimulate,  but  has 
also  an  action  on  the  muscular  fibre  itself.  Its  subsequent  ap- 
plication will  therefore  remove  the  effect  of  these  drugs,  and  they 
will  not  act  when  atropine  has  been  applied  first.  As  physo- 
stigmine stimulates  the  muscular  fibre  itself,  it  will  cause  con- 
traction in  an  eye  which  is  dilated  by  atropine  unless  the  action 
of  the  atropine  has  been  carried  to  such  an  extent  as  to  paralyse 
the  muscular  fibre. 

The  contraction  produced  by  muscarine  in  the  eye  of  the  cat 
is  so  great  as  to  reduce  the  pupil  to  a  mere  slit,  and  is  much 
greater  than  that  caused  by  physostigmine,  for  muscarine,  acting 
only  on  the  ends  of  the  oculo-motor,  produces  spasm  in  the 
sphincter  without  affecting  the  dilator,  while  physostigmine,  act- 
ing on  the  muscular  fibres,  is  said  to  stimulate  those  of  the 
dilator  as  well  as  the  sphincter,  and  thus  to  render  the  contrac- 
tion less  complete.2 

It  has  already  been  pointed  out,  however,  that  the  action  of 
atropine  is  not  confined  to  the  ends  of  the  oculo-motor  nerve,  but 
affects  the  muscular  fibre  itself,  and  thus  it  will  counteract  the 
effect  of  physostigmine,  which  it  would  not  do  if  it  acted  only  on 
the  nerves. 

Atropine  consists  of  the  combination  of  a  base,  tropine,  with 

1  Schmiedeberg,  Arzneimittellchre,  p.  71.        2  Schmiedeberg,  op.  cit. 


chap,  ix.]    ACTION  OF  DRUGS  ON  SPECIAL  SENSE.         223 

tropic  acid.  Tropine  itself  has  no  mydriatic  action,  but  when  an 
atom  of  hydrogen  in  it  is  displaced  by  an  acid  residue  it  acquires 
this  action.  A  number  of  combinations  of  tropine  with  different 
acids  have  been  artificially  prepared  by  Ladenberg,  who  terms 
them  tropeines.  Amongst  these  are  homatropine,  in  which  the 
tropine  is  combined  with  oxytoluylic  acid,  and  also  benzoyl-tropine. 
Atropine  appears  to  be  identical  with  daturine.  Hyoscyamine  is 
also  a  combination  of  tropine  with  tropic  acid,  but  it  appears  to 
be  only  isomeric  with  and  not  identical  with  atropine,  though  it 
seems  to  be  identical  with  duboisine. 

Action  of  Drugs  on  Accommodation. — The  accommodation 
of  the  eye  depends  upon  the  ciliary  muscle.  When  the  eye  is  at 
rest  the  lens  is  flattened  by  the  elastic  tension  of  the  zonule  of 
Zinn.  During  accommodation  for  near  objects  the  ciliary  muscle 
draws  the  zonule  forward  and  allows  the  lens  to  become  more 
convex.  The  ciliary  muscle  is  innervated  by  the  third  nerve : 
the  centre  for  it  appears  to  be  in  the  posterior  part  of  the  floor  of 
the  third  ventricle.  Those  drugs  which  affect  the  iris,  also  affect 
the  power  of  accommodation.  Their  action  on  the  iris  and  on 
accommodation  do  not,  however,  always  begin  at  the  same  time, 
nor  have  they  the  same  duration.  The  action  of  physostigmine 
and  atropine  on  accommodation  usually  begins  after,  and  passes 
away  long  before,  the  affection  of  the  pupil. 

Action  on  intra-ocular  pressure. — The  intra-ocular  pressure 
depends  greatly  on  the  amount  of  fluid  contained  in  the  vitreous, 
and  this  in  turn  is  determined  by  two  factors  : — 

(1)  The  amount  of  fluid  secreted  by  the  ciliary  body. 

(2)  The  freedom  with  which  fluid  escapes  at  the  angle  of  the 
anterior  chamber. 

The  aqueous  humour  and  the  fluid  which  nourishes  the 
vitreous  and  crystalline  lens  are  chiefly  secreted  by  the  ciliary 
processes.  It  ultimately  passes  out  from  the  anterior  chamber  of 
the  eye  by  a  number  of  small  openings  (/,  Pig.  75)  close  to  the 
junction  of  the  cornea  and  iris  into  the  canal  of  Schlemm 
(c,  s,  Fig.  75),  thence  into  the  anterior  ciliary  veins.  Some  of 
it  also  passes  into  the  perichoroidal  space,  and  out  through  the 
lymphatics. 

The  intra-ocular  pressure  may  be  increased  by  (a)  more  rapid 
secretion  from  the  ciliary  processes,  or  (b)  interference  with  its 
outward  flow  from  the  eye,  or  (c)  by  increased  quantity  of  blood 
in  the  vessels  of  the  iris.  It  may  be  diminished  by  the  contrary 
conditions. 

More  rapid  secretion  from  the  ciliary  process  probably  takes 
place  under  nervous  conditions  which  are  not  at  present  well 
known.  Interference  with  the  flow  of  the  aqueous  humour^  out 
of  the  anterior  chamber  may  occur  in  aquo-capsulitis,  in  which 
the  openings  from  the  anterior  chamber  into  the  spaces  of 
Fontana  are  occluded  by  a  coating  of  inflammatory  lymph  ;  also 


224  PHAKMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

in  glaticoma  where  these  openings  are  shut  by  the  iris  being  pressed 
forward  against  the  cornea,  as  in  Fig.  75,  and  in  iritis  where  the 
iris  is  much  congested  and  the  communication  between  the 
posterior  and  anterior  chambers  is  interrupted  by  complete  ad- 
hesion of  the  pupillary  edge  of  the  iris  to  the  anterior  capsule 
of  the  lens  (total  posterior  synechia).  The  secretion  is  probably 
diminished  by  the  action  of  atropine.  In  glaucomatous  states 
where  the  periphery  of  the  iris  lies  in  contact  with  the  cornea 
the  outward  flow  through  the  spaces  of  Fontana  may  often  be 
increased  by  Calabar  bean,  which,  by  causing  contraction  of  the 
circular  fibres  of  the  iris,  flattens  the  arch  of  the  iris  and,  drawing 
it  away  from  the  cornea,  reopens  the  contracted  angle  between 
the  cornea  and  iris,  and  permits  the  passage  of  fluid  through  the 
spaces  of  Fontana.1 

There  are  few  or  no  experiments  on  the  tension  in  the  vitreous 
humour  of  the  eye,  though  by  the  term  intra-ocular  tension  is 
usually  intended  the  pressure  in  the  vitreous  humour.      The 


Fig.  76.— This  diagram  (  vhich  I  owe  to  the  kindness  of  Mr.  J.  Tweedy)  represents  a  section  througu- 
tlie  corneo-scleral  region,  ciliary  body  and  iris,  of  a  healthy  eye  (left  side),  and  of  a  glaucomatous 
eye  (right  side)  :  A,  cornea  ;  s,  sclerotica ;  i,  iris  ;  /,  spaces  of  Fontana  ;  c  s,  canal  of  Schlemm.  In 
the  glaucomatous  eye  the  ciliary  body  is  atrophied,  and  the  iris  lies  against  the  cornea,  prevent, 
ing  the  escape  of  fluids  through  the  spaces  of  Fontana  and  canal  of  Schlemm. 

degree  of  intra-ocular  tension  is  usually  ascertained  by  pressing 
the  finger  secundum  artem  upon  the  eye  and  observing  whether  it 
is  harder  or  softer  than  usual,  or  by  pressing  upon  the  sclerotic 
with  an  ivory  point  attached  to  a  registering  spring,  and  noticing 
the  pressure  required  to  produce  an  indentation.  These  methods 
of  experiment  are  valuable  clinically,  but  the  tension  can  be 
more  exactly  ascertained  in  animals  by  passing  a  small  trocar 
into  the  anterior  chamber  and  connecting  it  with  a  manometer. 
The  results  of  experiments  even  by  this  method  are  not  entirely  in 
accordance.  The  most  recent  ones  by  Graser 2  appear  to  show  that 
the  tension  depends  to  a  great  extent  upon  the  height  of  the 
blood-pressure  generally :  contraction  of  the  pupil  diminishes, 
and  dilatation  increases  the  intra-ocular  tension.  Eserine  causes 
temporary  increase  at  first,  but  after  contraction  of  the  pupil 
comes  on,  the  tension  is  diminished.    Atropine  in  doses  sufficient 


J.  Tweedy,  Practitioner,  Nov.  1883,  vol.  xxxi.  p.  321. 
Graser,  Archiv  f.  exp.  Path.  u.  Pharm.,  Bd.  xvii.  Heft  5. 


chap,  ix.]     ACTION  OP  DBUGS  ON  SPECIAL  SENSE.         225 

to  dilate  the  pupil  increases  the  tension.  The  precise  effect  of 
atropine  on  intra-ocular  tension  in  man  is  disputed.  From 
clinical  observation  the  truth  would  seem  to  be  that  in  a  per- 
fectly healthy  eye  and  in  ordinary  iritis  atropine  and  other 
mydriatics  diminish  tension,  whereas  they  increase  the  tension 
when  the  anterior  chamber  is  shallow  from  narrowing  of  the 
iridic  angle.  In  glaucomatous  states  atropine  and  other  my- 
driatics almost  always  rapidly  increase  tension.  This  action  of 
atropine  and  its  allies  not  only  makes  them  dangerous  in  cases 
of  glaucoma,  but  where  this  disease  has  been  impending  it  has 
been  at  once  brought  on  by  their  use.  From  its  power  to 
diminish  tension  eserine  is  useful  in  glaucoma. 

Uses  of  Mydriatics  and  Myotics. — Belladonna  is  employed 
locally  for  its  sedative  action,  to  relieve  pain  and  allay  irritation 
and  inflammation  in  the  conjunctiva,  cornea,  choroid,  or  iris. 

Mydriatics  and  myotics  are  used  not  only  for  their  action 
upon  the  pupil  but  for  their  action  upon  accommodation  and 
intra-ocular  pressure. 

Mydriatics  are  employed  to  dilate  the  pupil  for  the  purpose 
of  facilitating  ophthalmoscopic  examination,. assisting  the  detec- 
tion of  cataract  commencing  in  the  periphery  of  the  lens,  or 
allowing  the  patient  to  see  past  the  edge  of  a  cataract  or  corneal 
opacity  when  this  is  central  in  position,  and  obstructs  the  vision 
with  a  pupil  of  normal  size.  They  are  used  to  prevent  prolapse 
of  the  iris,  or  to  restore  it  to  its  normal  position  when  already 
prolapsed  in  cases  of  perforating  ulcer  or  mechanical  lesion  of 
the  cornea.  They  are  employed  in  iritis  to  afford  rest  to  the 
inflamed  tissues  of  the  eye,  and  to  keep  the  iris  as  far  as  possible 
off  the  surface  of  the  lens  and  prevent  adhesions  of  its  posterior 
surface  to  the  anterior  surface  of  the  lens. 

Mydriatics  are  employed  to  paralyse  the  ciliary  muscle,  and 
thus  destroy  the  power  of  accommodation  in  order  to  test  the 
condition  of  the  refractive  media  of  the  eye  in  cases  of  astig- 
matism, or  in  cases  where  the  patients  either  suffer  from  spasm 
of  the  ciliary  muscle  or  are  unable  voluntarily  to  relax  the 
accommodation . 

Myotics  are  used  to  counteract  the  effect  of  mydriatics  which 
have  been  previously  employed,  or  in  mydriasis  following  a  blow 
or  paralysis  of  the  third  nerve.  They  are  used  also  to  counteract 
deficiency  in  tone  of  the  ciliary  muscle,  as  in  paralysis  of  ac- 
commodation consequent  on  diphtheria,  asthenopia,  a  blow  on 
the  eye,  &c. 

Myotics  are  useful  in  cases  of  threatening  and  commencing 
glaucoma  and  often  even  in  more  advanced  cases  of  glaucoma, 
from  their  power  to  lessen  intra-ocular  tension.  As  a  temporary 
expedient  they  are  often  of  the  greatest  service  in  cases  of  acute 
glaucoma.  So,  also,  if  perchance  the  instillation  of  atropine 
have  induced  glaucoma,  myotics  will  not  only  counteract  the 

Q 


226  PHARMACOLOGY  AND   THERAPEUTICS,      [sect.  I. 

mydriasis,  but  often  rapidly  restore  the  intra-oeular  tension  to 
the  normal  standard.1 

Mydriatics  and  myotics  may  be  employed  alternately  in  order 
to  ascertain  the  presence  of  any  adhesions  of  the  iris,'  and  to 
break  them  down  if  present. 

In  glaucoma  the  intra-ocular  tension  within  the  anterior 
chamber  is  greatly  increased,  and  the  increase,  according  to 
Tweedy,  is  due  to  the  natural  channel  of  escape  for  the  aqueous 
humour  through  the  spaces  of  Fontana  and  the  canal  of  Schlemm 
being  obstructed  by  the  iris  lying  against  the  cornea.  This 
condition  is  relieved  by  myotics,  which,  by  causing  contraction 
of  the  pupil,  draw  the  iris  away  from  the  cornea,  and  thus  allow 
the  fluid  to  escape  through  the  spaces  of  Fontana.  When  the 
anterior  chamber  of  the  eye  is  shallow  and  the  iris  is  lying  close  to 
the  cornea,  so  as  nearly,  though  not  quite,  to  obstruct  the  spaces  of 
Fontaaia,  atropine  may  induce  an  attack  of  glaucoma  by  dilating 
the  pupil  and  thus  packing  the  tissue  of  the  iris  into  the  angle 
between  it  and  the  cornea,  so  as  to  render  the  obstruction  to  the 
spaces  of  Fontana  complete. 

Action  of  Cocaine. — Cocaine,  when  applied  locally  to  the  eye, 
has  several  actions.  It  produces  local  anaesthesia,  dilatation  of 
the  pupil,  and  relaxation  with  more  or  less  complete  paralysis 
of  the  ciliary  muscle.  When  two  to  three  drops  of  a  4-per  cent, 
solution  are  applied  to  the  eye  at  intervals  of  five  minutes,  such 
complete  local  anaesthesia  of  the  cornea,  conjunctiva,  and  his  is 
produced  in  twenty  to  thirty  minutes  as  to  allow  operations  to  be 
performed  on  the  eye.  At  the  same  time  the  cocaine  causes  con- 
striction of  the  superficial  vessels,  producing  blanching  of  the 
conjunctiva.  The  dilatation  of  the  pupil  is  great,  is  quickly 
attained,  and  differs  from  that  produced  by  atropine  in  the  fact 
that  the  cocainised  pupil  reacts  to  light  and  accommodation.  The 
mydriasis  is  probably  due  to  stimulation  of  the  ends  of  the  sympa- 
thetic in  the  iris,  for  cocaine  will  not  produce  any  mydriatic  effect 
after  the  cervical  sympathetic  has  'been  cut  for  such  a  length  of 
time  as  to  allow  degeneration  of  the  peripheral  ends  to  occur, 
nor  has  stimulation  of  the  cervical  sympathetic  any  effect  in 
increasing  the  ad  maximum  cocaine  mydriasis.  That  the  third 
nerve  is  not  paralysed  is  shown  by  the  fact  that  stimulation  of 
it  produces  contraction  in  the  cocainised  pupil.  A  similar  effect 
follows  local  stimulation  of  the  sphincter  pupillse.  That  the 
action  of  cocaine  is  exerted  on  the  peripheral  ends  and  not  on  the 
centres  of  the  sympathetic  is  shown  by  the  fact  that  section  of  the 
cervical  sympathetic  does  not  alter  the  pupil  which  is  fully  dilated 
by  cocaine,  and  cocaine  induces  mydriasis  in  an  exsected  eye.2 

Action  of  Drugs  on  the  Retina.— By  a  comparison  of  the 
retina  of  a  frog  kept  in  darkness  with  one  exposed  to  light,  it  has 


Tweedy,  loc.  cii.  '  Jessop,  Proc.  Roy.  Soc,  1885. 


cSap.  ix-1    ACTION  OF  DEUGS  ON  SPECIAL  SENSE.         227 

been  found  that  light  causes  not  only  the  internal  segments  of 
the  cones  •  and  rods 2  but  also  the  pigment-cells  of  the  retina  to 
contract,  so  that  the  external  parts  of  the  rods  and  cones  as  well 
as  the  pigment  are  drawn  away  from  the  external  towards  the 
internal  limiting  membrane  of  the  retina  (Fig.  766).  A  similar 
effect  is  produced  by  heat.2  The  retina  of  a  frog  which  has  been 
tetanised  by  strychnine  in  complete  darkness  has  an  appearance 


Pig.  76.— Shows  the  position  of  the  rods  and  pigment-cells  in  the  retina  of  the  frog :  a,  after  the 
animal  has  been  kept  in  complete  darkness  for  one  or  two  days ;  6,  after  it  has  been  exposed  to 
diffused  daylight  for  five  or  ten  minutes,  after  being  kept  in  darkness  for  twenty-four  hours ; 
c,  after  exposure  to  light  as  in  b,  but  for  half  an  hour  instead  of  a  few  minutes.  This  also  repre- 
sents the  position  of  the  rods  and  pigment-cells  in  strychnine  tetanus. 

similar  to  that  of  a  retina  which  has  been  exposed  to  full  day- 
light, the  strychnine  haying  caused  extreme  contraction  of  the 
rods,  cones,  and  pigment-cells  (Fig.  76c).  A  similar  effect  is 
produced  by  tetanising  the  eye  itself  either  by  induced  currents 
in  the  dark,  or  while  it  is  still  in  the  head  or  immediately 
after  its  excision.  Curare  neither  hinders  this  action  nor  pro- 
duces it. 

Action  of  Drugs  on  the  Sensibility  of  the  Eye. — The 
sensitiveness  of  the  eye  to  impressions  is  increased  by  strychnine, 
the  field  of  vision  becoming  larger,  and  the  sight  more  acute,  so 
that  objects  can  be  distinctly  observed  at  a  greater  distance,  and 
the  field  of  colour  is  increased  for  blue.  This  action  appears  to 
be  to  a  certain  extfent  local,  as  it  occurs  more  distinctly  on  that 
side  where  the  strychnine  has  been  injected  hypodermically. 
The  sense  of  colour  is  affected  in  a  remarkable  way  by  santonin, 
which  at  first  causes  objects  to  appear  somewhat  violet  and  after- 
wards of  a  greenish-yellow.  The  yellow  colour  has  been  ascribed 
to  staining  of  the  media  of  the  eye  by  santonin,  as  it  becomes 
yellow  when  exposed  to  the  light ;  others  again  have  supposed 


1  Engelmann  (and  von  Genderen  Stort),  Pflilger's  Archiv,  xxxv.  p.  498. 
1  Gradenigo,  jun.,  Allg.  Wiener  med.  Ztg.,  1885,  No.  29. 

«  2 


228 


PHAEMACOLOGY  AND  THEKAPEUTICB.      (sect.  i. 


the  alteration  in  the  apparent  colour  of  objects  to  be  due,  first  to 
a  stimulation,  and  then  to  a  paralysis  of  those  constituents  of  the 
retina  by  which  the  violet  colour  is  perceived. 

The  sensibility  of  tbe  eye  for  red  and  green  appears  to  be 
sometimes  diminished  by  physostigmine. 

Action  of  Drugs  in  Producing  Visions.— It  may  be  well 
here  to  mention  the  effect  of  some  drugs  in  causing  subjective 
sensations  of  sight,  although  these  probably  depend  rather  upon 
the  action  of  the  drugs  on  the  brain,  than  on  the  eye  itself.  The 
centres  for  sight,  according  to  Ferrier,  are  the  angular  gyrus 
(14  and  15,  Fig.  68,  p.  185),  and  the  occipital  lobes.  In  delirium 
tremens  arising  from  alcoholic  excess  the  patients  often  complain 
much  of  visions  of  the  most  disagreeable  character,  which  often 
take  the  form  of  demons  or  of  animals. 

Cannabis  indica  produces  in  some  persons,  though  not  in  all, 
visions  which  may  be  pleasant  or  laughable.  These  chiefly  occur 
just  'before  sleep.1 

Salicylate  of  sodium  in  some  persons  tends  to  cause  most 
disagreeable  visions  whenever  the  eyes  are  shut,  and  I  have  seen 
it  have  this  effect  even  in  such  a  small  dose  as  five  grains. 
Large  doses  of  digitalis  may  cause  subjective  sensations  of  light, 
and  after  taking  nearly  one  grain  of  digitalin  in  the  course  of 
forty-eight  hours  I  suffered  from  the  centre  of  the  field  of  vision 
being  occupied  by  a  bright  spot  surrounded  by  rainbow  colours. 
Digitalin  when  introduced  into  the  eye  locally  causes  at  first 
smarting  and  lacrimation,  which  soon  passes  off,  but  after  four 
or  five  hours,  when  a  light  is  looked  at,  a  halo  is  seen  surround- 
ing it,  which  is  not  improbably  due  to  some  opalescence  in  the 
cornea.2 

Toxic  Amblyopia. — Belladonna  taken  internally  in  sufficient 
quantity  causes  dilatation  of  the  pupil  and  misty  vision.  Alcohol, 
tobacco,  quinine,  and  lead  all  cause  failure  of  the  power  of  vision 
for  form  and  for  certain  colours,  as  well  as  limitation  of  the  field 
of  vision  either  in  the  centre  or  the  periphery.  These  symptoms 
are  at  first  functional,  but  if  not  relieved  they  may  be  the  pre- 
cursors of  actual  anatomical  changes. 

Action  of  Drugs  on  Hearing. 

The  sense  of  hearing  depends  on  the  transmission  of  sonorous 
vibrations  from  the  air  to  the  auditory  nerve  by  means  of  the 
membrana  tympani  and  the  ossicles  of  the  ear,  and  upon  the 
perception  of  those  vibrations  by  the  brain. 

The  centre   for    hearing,   according  to  Ferrier,   is   in  the 


1  Compare  Sohrofi,  Pharmacologie,  4th  ed.  p.  535,  and  Wood,  Materia  Medica, 
3rd  ed.  p.  236. 

2  Lauder  Brunton,.  On  Digitalis,  &c. 


chap,  nc]    ACTION  OP  DEUGS  ON  SPECIAL  SENSE.  229 

superior  temporo-sphenoidal  convolution  (16,  Fig.  68,  p.  185). 
It  is  probable  that  subjective  sounds  not  depending  on  disturb- 
ance of  the  auditory  apparatus,  such  as  the  sounds  of  voices,  &c, 
heard  in  delirium  or  mania,  or  as  the  prodromata  of  an  epileptic 
fit  in  certain  individuals,  or  during  intoxication  by  cannabis 
indica,  are  due  to  irritation  of  these  eentres. 

The  sense  of  hearing  may  be  dulled  by  any  interference  with 
the  passage  of  the  sound  into  the  ear,  as  by  wax  in  the  auditory 
meatus,  by  disease  of  the  auditory  nerve  or  of  the  brain  itself. 

The  hearing  may  be  rendered  more  acute  by  the  removal  of 
any  obstacle  in  the  way  of  transmission  of  sound  to  the  auditory 
nerve,  or  by  drugs  which  increase  the  excitability  of  the  auditory 
nerve  or  of  the  brain ;  thus  the  wax  may  be  removed  by  simply 
syringing ;  thickness  and  catarrh  of  the  Eustachian  tube  which 
interfere  with  vibrations  in  the  middle  ear  may  be  lessened  by 
the  inhalation  of  camphor  and  ammonia,  or  by  the  application 
of  a  solution  of  ammonium  chloride  and  sodium  bi-carbonate  to 
the  posterior  nares  either  by  the  spray  or  nasal  douche.  The 
excitability  of  the  auditory  nerve  or  of  the  brain  is  increased  by 
strychnine,  which  renders  the  hearing  more  acute. 

Subjective  noises  in  the  ear,  such  as  humming,  buzzing,  or 
ringing,  are  often  very  troublesome.  Bubbling  noises  may  be 
due  to  mucus  in  the  Eustachian  tube.  Buzzing  or  humming 
are  probably  generally  caused  by  vascular  congestion  either  of 
the  external  meatus,  of  the  middle  ear,  or  of  the  Eustachian 
tube.  Where  the  bubbling  noises  are  due  to  the  presence  of 
mucus  they  may  be  to  a  considerable  extent  removed  by  washing 
out  the  mucus  with  a  solution  of  carbonate  of  sodium  applied  by 
a  nasal  douche.  Noises  in  the  ears  due  to  hyperemia  may  be 
lessened  or  removed  by  cholagogue  purgatives  and  by  hydro- 
bromic  acid.  Where  chronic  thickening  of  the  membrane  is 
present,  relief  is  usually  afforded  by  iodide  of  potassium  or 
iodide  of  ammonium,  both  applied  locally  and  taken  internally. 
Subjective  noises  in  the  ears  are  caused  by  quinine  in  large 
doses,  and  also  by  salicylate  of  sodium.  Both  of  these  drugs 
have  their  effect  upon  the  ear  to  a  great  extent  neutralised  by 
hydrobromic  acid,  and  ergot '  is  said  to  have  a  similar  power 
to  prevent  or  remove  the  unpleasant  singing.  It  is  uncertain 
whether  the  singing  caused  by  quinine  and  salicylates  is  due  to 
their  action  on  the  auditory  apparatus,  or  the  cerebral  centres ; 
but  the  fact  that  in  larger  doses  they  may  cause  delirium  in- 
dicates that  even  the  earlier  symptom  of  buzzing  in  the  ears 
may  be  due,  in  part  at  least,  to  their  action  on  the  cerebral 
centres. 

1  Schilling;  Aertzl.  Intelligenzblalt,  1883. 


230  PHAEMACOLOGY  AND  THERAPEUTICS,      [sect.  i. 


Action  of  Drugs  on  Smell. 

Many  drugs,  such  as  musk  and  ethereal  oils,  have  a  marked 
and  characteristic  smell,  due  to  their  effect  upon  the  terminal 
branches  of  the  olfactory  nerve.  This  nerve  is  soon  exhausted, 
so  that  in  a  very  short  time  the  smell  is  no  longer  perceived  with 
anything  like  the  intensity  it  was  at  first.  Such  smells  as  these 
just  mentioned  cannot  be  perceived  by  persons  suffering  from 
anosmia,  but  certain  drugs,  such  as  ammonia  or  acetic  acid, 
can  be  recognised  by  them.  The  reason  of  this  is  that  although 
such  persons  are  incapable  of  perceiving  any  true  smell,  the 
nasal  branches  of  the  fifth  nerve  are  irritated  by  pungent  vapours, 
and  thus  produce  a  certain  kind  of  sensation.  The  power  of 
distinguishing  smells  seems  to  be  increased  by  strychnine ;  which 
appears  at  the  same  time  to  render  such  disagreeable  odours  as 
those  of  asafcetida,  garlic,  and  valerian  agreeable.  This  effect 
may  be  due  to  the  action  of  strychnine  on  the  olfactory  apparatus, 
but  it  is  very  probably  due  rather  to  the  action  of  the  drug  on 
the  cerebral  centre  for  smell,  which,  according  to  Ferrier,  is 
situated  at  the  tip  of  the  temporo-sphenoidal  lobe.  The  power 
•  to  distinguish  smells  is  diminished  by  such  drugs  as  lessen  the 
sensibility  of  the  brain,  or  by  those  which  cause  alterations  in 
the  nasal  mucous  membrane,  as,  for  example,  iodide  of  potassium 
given  in  such  doses  as  to  produce  coryza. 

Action  of  Drugs  on  Taste. 

Most  of  the  substances  used  in  medicine  have  a  strong  taste, 
and  many  a  very  unpleasant  taste. 

What  is  usually  termed  taste  frequently  depends  on  a  mixture 
of  taste  and  smell,  and  if  the  sense  of  smell  is  abolished  for  the 
time  being,  the  characteristic  taste  of  the  substance  cannot  be 
distinguished.  This  is  the  reason  why  castor-oil,  which  owes  its 
nauseous  taste  almost  entirely  to  its  odour,  can  be  swallowed 
without  being  so  readily  distinguished  if  the  nose  is  held  during 
the  act  of  swallowing.  In  addition  to  the  taste  they  produce  in 
the  mouth,  certain  substances  leave  an  impression  termed  '  after 
taste '  on  the  tongue  after  they  have  been  swallowed  or  ejected ; 
and  this  is  sometimes  quite  different  from  that  of  the  taste  of 
the  substance  itself :  thus  bitters  leave  a  sweet  after-taste  in  the 
mouth.  If  quinine  is  taken  in  a  nearly  neutral  solution,  it 
leaves  a  persistent  bitter  taste  from  the  sparingly  soluble  alka- 
loid being  precipitated  on  the  tongue  and  remaining  there  for  a 
length  of  time,  but  if  the  quinine  be  taken  with  excess  of  acid, 
so  as  to  keep  it  entirely  in  solution,  and  washed  out  of  the 
mouth  immediately  with  a  draught  of  water,  it  leaves  a  sweet 
after-taste. 


chap,  ix.]    ACTION  OF  DEUGS  ON  SPECIAL  SENSE.  231 

Some  substances  after  their  entrance  into  the  blood  are 
excreted  by  the  saliva  and  may  cause  a  somewhat  persistent 
taste  in  the  mouth ;  this  is  observable  in  the  case  of  iodide  of 
potassium. 

Iodine  appears  also  to  have  the  power  of  causing  other  sub- 
stances to  be  excreted  by  the  saliva,  when  they  are  combined 
with  it,  and  thus  Bernard  found  that  iodide  of  iron  was  secreted 
by  the  saliva,  though  lactate  of  iron  was  not ;  and  I  have  some- 
times thought  that  iodine  has  a  similar  effect  upon  quinine, 
because  I  have  very  frequently  noticed  patients  complain  of  a 
persistent  bitter  taste  in  their  mouth  when  I  have  given  quinine 
combined  with  iodide  of  potassium,  although  they  did  not  com- 
plain of  this  when  either  of  the  drugs  has  been  given  without 
the  other. 


232  PHARMACOLOGY  AND  THERAPEUTICS,      [seot.i. 


CHAPTER  X. 
ACTION  OF  DRUGS  ON  RESPIRATION. 

Respiratory  Stimulants  and  Depressants. 

It  is  usually  supposed  by  naturalists  that  in  the  descent  of  man 
from  some  organism  low  in  the  scale  of  existence,  he  has  passed, 
at  a  remote  period,  through  a  stage  resembling  the  Ascidians  or- 
Tunicata.  In  these  animals  respiration  is  maintained  by  water 
being  driven  through  a  perforated  sac  in  the  meshes  of  which 
the  nutritive  fluids  of  the  animal  circulate.  The  contractile 
motions  of  the  sac  by  which  the  circulation  of  fluid  is  maintained 
probably  depend  on  a  nervous  ganglion  situated  between  the 
oral  and  anal  apertures  as  represented  in  the  diagram  (Fig.  77). 
We  do  not  know  whether  or  not  this  ganglion  may  influence  the 
circulation  which  is  maintained  by  the  rhythmical  contractions  of 
the  simple  tube  which  serves  as  a  heart.  These  drive  the  fluid 
first  in  one  direction,  and  then  after  a  while  the  action  of  the 
tube  is  reversed,  and  its  contractions  drive  the  fluid  in  the  oppo- 
site direction.  This  ganglion  in  its  functions  would  correspond 
with  the  medulla  oblongata  in  the  vertebrata,  and  thus  the 
medulla  oblongata  may  be  looked  upon  as  a  lower  and  more 
fundamental  centre  than  the  brain  or  spinal  cord. 

We  see  this  more  distinctly  perhaps  by  looking  at  the  two 
diagrams  (Figs.  78  and  79)  representing  an  amphioxus  and  a 
fish.  In  the  amphioxus  respiration  is  kept  up  in  much  the  same 
way  as  in  the  ascidian,  the  water  passing  from  the  pharyngeal 
to  the  atrial  sac  and  through  the  atrial  aperture  or  abdominal 
pore.  There  is  no  head  and  no  organs  of  special  sense,  and  so 
we  have  no  brain  whatever.  But  the  body  is  elongated  so  as  to 
remind  us  of  an  ascidian,  having  its  ganglion  and  the  part  of  the 
body-wall  containing  it  so  much  extended  as  to  remove  the  anal 
considerably  from  the  oral  aperture.  The  muscles  of  this 
elongated  body  require  innervation,  and  thus  the  ganglionic  mass 
is  elongated  into  a  cord  called  the  myelon,  which  represents  the 
spinal  cord  as  well  as  the  medulla  oblongata.  In  ascidians  then 
we  have  a  mass  corresponding  to  the  medulla ;  in  the  amphioxus 
we  have  a  mass  corresponding  to  medulla  and  spinal  cord. 


chap,  x.]      ACTION  OF  DEUGS  ON  EESPIEATION.  '233 

In  a  fish  the  pharyngeal  or  branchial  sac,  instead  of  opening 
into  the  atrial  sac,  opens  directly  into  the  surrounding  water. 


Body  wall 

Serves  passing  from  the 
ganglion 


Pharyngeal  sao 

General  body-cavity 
Heart 


'  Oral  aperture. 

Part  of  body  wall    containing 

ganglion. 
Branchio-anal  or  atrial  aperture. 

1  Branchial  openings  in  the  sep- 
tum between  the  pharyngeal 
and  anal  sac. 


Intestine \-J. 


Fig.  77.— Diagram  of  an  Ascidian. 


Oral  aperture  — — 


Branchial  openings  | 

3/   — — . 


or  pharyngeal  sac 
Pharyngeal  sac 


Branchial  aperture  or 
abdominal  pore 

Ana}  aperture 


Mr Nose. 

Orrl 
aperture  "-"" 
Branchial 
apertures 

il 
>4 

wi               Brain. 

Nervous 
myelon. 

i 

[Ktf    \          cord 

Anal 

apertuie  — 

w, 

Fig.  78. — Diagram  of  Amphioxus.  'riie  water  enters  the 
oral  aperture,  passes  through  the  openings  in  the 
pharyngeal  sac  into  another  cavity,  whence  it 
escapes  by  the  abdominal  pore. 


Tia.  79.— Diagram  of  fish. 


We  have  a  head  and  organs  of  special  sense,  and  therefore  we 
have  a  large  nervous  mass  or  brain. 

In  these  three  members  of  the  animal  kingdom,  therefore,  we 
have  the  medulla  as  the  lowest  or  fundamental  centre,  next  the 
spinal  cord,  and  lastly  the  brain.  We  might  therefore  expect 
that  notwithstanding  the  apparently  higher  position  and  greater 
nearness  of  the  medulla  to  the  brain  than  to  the  spinal  cord, 
the  medulla  would  be  less  readily  affected  by  many  drugs  than 
the  cord  or  the  brain,  and  this  is  what  we  find  in  the  case 
of  such  drugs  as  alcohol,  ether,  or  morphine,  which  appear  to 
paralyse  the  nervous  centres  in  the  inverse  order  of  their  de- 
velopment— the  brain  first,  spinal  cord  next,  and  medulla  last. 

There  are  some  drugs,  however,  e.g.  aconite,  gelsemium,  and 


234  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  I. 

hydrocyanic  acid,  which  seem  to  have  a  special  paralysing  action 
on  the  respiratory  centre. 

If  we  look  at  the  ganglionic  mass  in  an  ascidian,  represented 
in  the  diagram,  we  shall  see  that  it  sends  some  fibres  to  the 
pharyngeal  sac  and  some  to  the  anal  sac.  If  these  two  sacs  were 
to  contract  together  they  would  oppose  each  other's  action,  and 
thus  the  passage  of  water  through  the  branchial  apertures  would 
be  stopped,  and  respiration  consequently  arrested.  They  must 
therefore  act  alternately,  and  this  alternate  action  is  regulated 
by  the  ganglion.  This  ganglion  consists  of  numerous  nerve-cells 
and  fibres.  As  some  of  these  have  a  more  special  connection 
with  the  pharynx,  the  group  which  they  form  may  be  called  the 
pharyngeal  centre  or  inspiratory  centre. 

Similar  arrangements  occur  in  higher  animals,  and  the  terms 
used  in  regard  to  their  nervous  system  may  lead  to  some  confu- 
sion of  thought ;  thus  we  speak  of  the  respiratory,  of  the  inspi- 
ratory, of  the  expiratory,  and  of  the  vomiting  centres. 

By  nerve-centres  we  simply  mean  the  groups  of  cells  and 
fibres  which  are  concerned  in  the  performance  of  certain  acts. 
They  are  not  necessarily  entirely  distinct  from  one  another,  and  the 
same  group  of  ganglionic  cells  may  form  a  part  of  several  centres. 
Thus  in  the  accompanying  diagram  (Fig.  80),  the  respiratory 
centre  includes  both  inspiratory  and  expiratory  centres,  and 
the  vomiting  centre  includes  some  ganglionic  groups  which  form 
part  of  the  inspiratory,  and  others  forming  part  of  the  expiratory 
centres,  besides  other  ganglion  groups  which  are  concerned  with 
the  simultaneous  dilatation  of  the  cardiac  orifice  of  the  stomach. 
On  analysing  this  subject  still  further  we  find  also  that  the 
inspiratory  centre  affects  many  muscles,  and  that  it  does  not 
always  affect  them  to  the  same  extent.  Thus  in  men  the  dia- 
phragm takes  a  more  active  share  in  inspiration  during  the  day 
than  the  thoracic  muscles.  During  sleep  the  diaphragm  takes 
a  much  less  active  part,  and  may  be  entirely  quiet,  while  the 
thoracic  muscles  are  more  active,  and  the  chest  rises  and  falls 
more  than  during  walking. 

The  inspiratory  centre  might  be  thus  still  further  divided 
into  thoracic  inspiratory  centre,  and  diaphragmatic  inspiratory 
centre. 

Such  subdivisions  appear  absurd  if  we  imagine  that  each 
centre  represents  a  distinct  nervous  mass,  and  we  become  puzzled 
to  understand  how  the  medulla  oblongata  can  contain  so  many 
distinct  centres  in  a  small  bulk.  But  if  we  remember  that  the 
word  '  centre '  simply  indicates  a  group  of  cells  and  fibres 
connected  with  the  performance  of  a  particular  act,  and  that  two 
centres  may  be  formed  by  the  same  ganglionic  groups  and  differ 
from  one  another  only  by  having  a  few  ganglion  cells  more  or 
less  which  alter  the  function  they  perform,  no  harm  is  done  by 
the  use  of  the  term. 


chap,  x.]      ACTION  OF  DEUGS  ON  EESPIEATION.  233 

The  act  of  respiration  consists  in  the  alternate  enlargement 
and  diminution  of  the  thoracic  cavity,  so  that  the  air  is  alter- 
nately inspired  and  expired. 


Vomiting  centre. 


Bespiratory  centre. 


Fig.  80.— Diagrammatic  representation  of  various  groups  of  ganglion  cells,  or  'centres'  in  the 
medu  la  oblongata.  The  arrows  indicate  the  directions  in  which  the  nerve-currents  pass  Those 
pointing  to  the  cells  indicate  sensory,  those  pointing  from  the  cells  indicate  motor  nerves 

I 

The  muscles  by  which  this  is  effected  in  ordinary  respiration 
are  the  diaphragm  and  intercostal  and  scaleni  muscles.  The 
diaphragm  descends,  and  the  intercostal  and  scaleni  muscles  raise 
the  ribs  during  inspiration. 

Expiration  is  normally  a  passive  act,1  and  is  not  performed 
by  muscular  action,  but  simply  by  the  tendency  of  the  dia- 
phragm and  thoracic  walls  to  return  to  the  position  of  the  equi- 
librium from  which  they  had  been  removed  during  inspiration, 
and  by  the  contraction  of  the  elastic  walls  of  the  air- vesicles  dis- 
tended by  inspiration. 

When  the  supply  of  oxygen  is  deficient,  other  muscles  are 
called  in  to  aid  the  inspiration.  Expiration  appears  to  be  a 
passive  act,  not  merely  in  ordinary  respiration,  but  even  in  dys- 
pnoea caused  by  the  absence  of  oxygen.  In  some  experiments 
by  Bernstein2  the  inspiration  and  expiration  were  equally 
increased  in  a  rabbit,  when  the  air  which  it  had  breathed  was 
replaced  by  hydrogen.  But  expiratory  efforts  are  required  both 
for  the  production  of  voice,  and  for  the  removal  of  irritants  from 
the  air-passages  by  coughing  or  sneezing ;  and  forcible  expira- 


1  Bernstein,  Archiv  f.  Anat.  u.  Physiol.,  1882,  p.  322. 
*  Ibid.,  op.  cit. 


236  PHARMACOLOGY  AND   THERAPEUTICS,      [sect.!, 

tion  is  produced  when  an  irritant  is  applied  to  the  mucous  mem- 
brane of  the  nose,  of  the  larynx,  trachea,  or  bronchi.  As  every 
one  who  has  drunk  a  bottle  of  soda-water  knows,  carbonic  acid  is 
an  irritant  of  considerable  power  to  these  mucous  membranes, 
and  when  it  is  breathed  instead  of  air  or  hydrogen  the  expiration 
becomes  much  more  powerful,  and  is  no  longer  a  passive  action, 
but  an  active  one,  performed  by  active  muscular  exertion. 

The  chief  respiratory  centre  is  situated  in  the  medulla  ob- 
longata close  to  the  end  of  the  calamus  scriptorius,  at  the  point 
designated  nceud  vital  by  Flourens,  because  destruction  of  this 
point  arrests  the? respiration  and  causes  death. 

It  extends  equally  on  both  sides  of  the  middle  line  in  the 
medulla,  each  half  regulating  the  breathing  on  the  same  side  of 
the  body.  It  has  been  supposed  to  be  double,  and  to  consist  of 
inspiratory  and  expiratory  centres  which  act  alternately,  but  it 
would  appear  that  in  ordinary  respiration  the  inspiratory  centre 
only  is  active. 

When  the  centre  is  injured  by  a  puncture,  as  in  Flourens' 
experiment,  or  when  one  half  of  it  is  destroyed,  breathing  usually 
stops  entirely,  but  if  the  respiration  be  kept  up  artificially  for 
several  hours,  the  normal  breathing  again  becomes  established ; 
and  the  prolonged  continuance  of  artificial  respiration  has  been 
recommended  by  Schiff  in  apoplexy. 

When  the  connection  between  this  centre  and  the  respira- 
tory muscles  is  cut  off  by  dividing  the  spinal  cord  just  below 
the  medulla,  respiration  usually  ceases  entirely,  so  that  at  first 
sight  it  would  seem  that  the  respiratory  centre  is  limited  to  the 
medulla. 

The  effects  of  strychnine  show  that  this  is  not  the  case.  This 
drug  greatly  increases  the  excitability  of  the  respiratory  centre, 
and  when  it  is  injected  into  the  blood  before  division  of  the  spinal 
cord,  the  respiratory  movements  still  continue  to  some  extent 
after  the  cord  has  been  divided.  When  it  is  injected  after  section 
of  the  cord,  the  respiratory  movements  which  had  ceased  again 
recommence  to  a  slight  degree. 

The  reason  appears  to  be  that  the  respiratory  centre  is  not 
limited  to  the  medulla,  but  extends  to  the  upper  part  of  the 
spinal  cord,  though  the  spinal  portion  is  of  itself  too  weak  to 
keep  up  the  respiratory  movements,  except  when  stimulated  by 
strychnine. 

The  amount  of  respiratory  work  which  this  centre  excites 
appears  to  depend  to  a  great  extent,  though  not  entirely,  upon 
the  condition  of  the  centre  itself. 

The  distribution  of  the  work  is  chiefly  determined  by  the 
irritation  of  one  or  other  of  the  afferent  nerves,  and  these  nerves 
also  influence  the  amount  of  work. 

The  centre  is  stimulated,  and  the  amount  of  work  it  does 
increased  by  a  venous  condition  of  the  blood  circulating  in  it. 


chap,  x.]      ACTION  OF  DEUGS.ON  EESPIEATION.  287 

An  arterial  condition  of  its  blood  lessens  or  completely  abolishes 
its  activity,  so  that  when  the  blood  is  highly  aerated  by  forced 
artificial  respiration,  a  condition  of  apncea  is  produced,  in  which 
no  spontaneous  respiratory  movements  occur. 

_  This  condition  is  much  more  readily  induced  when  the  excit- 
ability of  the  respiratory  centre  is  lessened  by  drugs.  In  an 
animal  poisoned  by  chloral,  for  example,  it  is  very  easy  to  induce 
it,  and  it  lasts  for  a  long  time. 

When  the  respiratory  centre  is  excited,  as  by  the  injection 
of  emetine  or  apomorphine  into  the  circulation,  it  is  difficult  or 
impossible  to  produce  this  condition. 

It  is  uncertain  whether  the  stimulation  which  the  venosity  of 
the  blood  produces  is  due  chiefly  to  the  absence  of  oxygen  or  to 
the  presence  of  carbonic  acid.  Possibly  it  may  also  be  due  to  the 
products  of  imperfect  combustion  in  the  venous  blood.  Or  all 
these  three  causes  may  share  in  the  stimulation,  though  to  what 
extent  each  does  so  is  not  known. 

According  to  Bernstein,  want  of  oxygen  appears  to  stimulate 
the  inspiratory  and  the  presence  of  carbonic  acid  to  stimulate  the 
expiratory  centre.1 

As  the  blood  becomes  venous  the  activity  of  the  respiratory 
centre  increases,  the  respirations  becoming  quicker  and  deeper,  and 
the  accessory  respiratory  muscles  are  thrown  into  action.  This 
condition  is  called  dyspnoea.  Finally  the  excitement  extends 
to  all  the  muscles  of  the  body  and  we  get  general  convulsions, 
which  have  usually  an  opisthotonic  character.  The  eyeballs 
very  often  protrude  during  these  convulsions,  and  the  blood- 
pressure  rises  greatly  from  stimulation  of  feympathetic  and  vaso- 
motor centres  in  the  medulla. 

After  the  convulsions  cease,  the  animal  usually  lies  motion- 
less, and  the  heart  as  a  rule  continues  to  beat  for  a  short  time 
after  the  respirations  have  ceased. 

The  excessive  venosity  of  the  blood  in  this  condition  has 
paralysed  the  nerve-centres,  but  if  artificial  respiration  be  now 
commenced  and  the  blood  becomes  gradually  aerated,  the  condi- 
tions just  described  are  again  passed  through  in  the  reverse 
order  :  convulsions  first  reappearing,  then  dyspnoea,  next  normal 
breathing,  and,  if  the  respiration  be  pushed  far  enough,  apncea'. 

Asphyxial  convulsions  only  occur  in  warm-blooded  animals, 
and  not  in  frogs,  and  when  we  find  that  any  drug  produces  con- 
vulsions in  mammals  and  not  in  frogs  we  usually  assume  that 
the  convulsions  are  due  to  asphyxia  produced  by  the  action  of  the 
drug  on  the  respiration  or  circulation,  and  not  to  a  direct  irri- 
tant action  upon  the  motor  centres.  If,  on  the  other  hand,  we 
find  that  the  convulsions  occur  in  frogs  as  well  as  in  mammals, 
the  presumption  is  in  favour  of  their  being  due  to  the  direct 
irritant  action  of  the  drug  on  motor  centres. 

1  Bernstein,  op.  cit.  p.  324. 


23S  PHAEMACOLOGY  AND  THERAPEUTICS,     [sect,  u 

Blood  becomes  venous  when  the  external  respiration  or  inter- 
change of  gases  between  it  and  the  external  air  is  arrested  while 
internal  respiration  continues. 

Internal  respiration  or  interchange  of  gases  occurs  between 
tbe  blood  and  the  tissues  outside  the  vessels  which  are  consuming 
oxvgen  and  deriving  it  from  the  blood.  But  the  blood  although 
fluid  is  itself  a  tissue  and  likewise  consumes  oxygen,  so  that  it 
will  become  venous  if  left  to  itself  in  a  thoroughly-stoppered  glass 

bottle. 

External  respiration  may  be  arrested  or  diminished  by — 

(1)  Interfering  with  the  access  of  air  to  the  blood ;  or 

(2)  „  „      „        ,,      ,,  blood  to  the  air ;  or 

(3)  „  „      „    power  of  the  blood  to  take  up 

and  give  off  oxygen. 
The  access  of  air  to  the  blood  may  be  prevented  by  obstruction 
to  the  air-passages  or  alteration  in  the  structure  of  the  lung ;  thus 
anaesthetics  may  obstruct  respiration  by  allowing  vomited  matters 
to  enter  the  trachea  and  plug  it  mechanically.  Apomorphine  may 
lead  to  obstruction  of  the  bronchi  by  profuse  secretion  from  the 
mucous  membrane,  and  large  doses  of  antimony  may  cause  con- 
solidation of  the  lung. 

Air  may  be  prevented  from  reaching  the  blood  by  any  obstruction  in  the 
respiratory  passages. 

The  respiratory  passages  may  be  obstructed  by  spasmodic  closure  of  the 
glottis  or  of  the  nostrils  in  rabbits  when  an  irritating  vapour  is  inspired. 
This  source  of  obstruction  is  easily  avoided  by  putting  a  cannula  into  the 
trachea  and  allowing  the  vapour  to  be  inspired  through  it.  Another  source  of 
obstruction  is  the  formation  of  plugs  of  mucus  or  clots  of  blood  in  the  trachea 
or  in  the  cannula,  which  has  been  introduced  into  it.  Occasionally  a  plug  of 
mucus,  and  sometimes  a  clot  of  blood,  forms  in  the  tracheal  cannula  and 
seriously  impedes  the  respiration,  whether  natural  or  artificial,  without 
being  perceived  by  the  experimenter.  In  order  to  be  sure  that  such  an  oc- 
currence has  not  taken  place  and  vitiated  the  results,  it  is  always  advisable, 
on  removing  the  cannula  from  the  trachea  at  the  end  of  an  experiment,  to 
blow  through  it  and  see  that  its  lumen  is  perfectly  unobstructed. 

Access  of  air  to  the  blood  may  be  prevented  also  by  paralysis 
of  the  muscles  of  respiration;  thus  curare  will  produce  it  by 
paralysing  the  ends  of  the  motor  nerves,  hydrocyanic  acid 
by  paralysing  the  respiratory  centre,  and  snake  poison  by 
paralysing  both. 

The  blood  may  be  prevented  from  reaching  the  lungs  by  arrest 
of  the  circulation  either  local  or  general,  and  may  thus  become 
venous,  either  locally  or  generally. 

The  venosity  of  the  blood  circulating  in  the  medulla  may  be 
altered  locally  without  any  change  in  the  rest  of  the  body. 
Thus  if  the  carotid  and  vertebral  arteries  are  tied,  the  blood 
stagnates  in  the  vessels  of  the  medulla,  and  there  becoming  venous 
causes  dyspnoea  and  convulsions,  which  again  disappear  when  the 
ligatures  are  loosened  and  the  circulation  re-established. 


chap.  x.j     ACTION  OF  DEUGS  ON  EESPIEATION.  239 

Dyspnoea  and  convulsions  are  likewise  produced  by  alteration 
in  the  general  circulation,  e.g.  by  loss  of  blood,  as  is  seen  when 
an  animal  is  bled  to  death,  or  when  the  supply  of  blood  in  the 
arteries  is  greatly  diminished  by  ligature  of  the  portal  vein,  which 
causes  the  blood  to  accumulate  and  stagnate  in  the  capacious 
veins  of  the  intestine. 

Stoppage  of  the  heart,  either  by  ligature  directly  applied  to 
it  or  by  the  action  of  drugs  upon  it,  causes  asphyxia  and  convul- 
sions. 

Arrested  circulation  through  the  pulmonary  vessels  by  emboli 
has  a  similar  action.  This  sometimes  leads  to  error  in  regard  to 
the  action  of  drugs  when  these  are  injected,  as  is  often  done,  into 
the  jugular  vein. 

If  they  contain  solid  particles,  these  mav  give  rise  to  embolism 
in  the  pulmonary  arteries  and  lead  to  the  belief  that  the  drug  has 
a  tetanising  action,  when,  as  a  matter  of  fact,  it  has  nothing  of 
the  kind.  Thus,  in  making  an  experiment  on  condurango,  I 
injected  an  infusion  into  the  jugular  vein  of  a  rabbit,  and  it 
rapidly  died  with  symptoms  resembling  those  of  strychnine-poison- 
ing. The  cause  of  this,  however,  was  simply  embolism  of  the 
pulmonary  vessels,  due  to  undissolved  particles  in  the  infusion, 
and  when  this  was  avoided  by  injecting  the  drug  into  the  peri- 
toneal cavity,  no  symptom  whatever  was  produced.  Gianuzzi, 
in  his  experiments  on  this  drug,  appears  to  have  fallen  into  the 
same  error  as  I  did  at  first. 

Altered  condition  of  the  blood  also  gives  rise  to  dyspnoea,  as 
is  seen  in  the  breathlessness  of  anaemia,  where  the  blood  is  unable 
to  take  up  the  quantity  of  oxygen  necessary  for  any  exertion,  and 
the  patient  pants  violently  after  any  quick  movement,  such  as 
going  up  stairs. 

Dyspnoea  and  even  convulsions  are  also  caused  by  nitrites,  e.g. 
nitrite  of  amyl  or  sodium,  which  lessen  the  power  of  the  blood  to 
give  off  oxygen,  and  by  carbonic  oxide,  which  replaces  the  oxygen 
in  the  blood. 

It  must  be  remembered,  however,  that,  whatever  may  be  the 
remote  cause  of  dyspnoea,  its  direct  cause  is  the  condition  of  the 
nerve-cells  in  the  medulla,  and  if  these  are  unable  to  take  up 
oxygen,  and  give  off  carbonic  acid  to  the  blood,  dyspnoea  may 
occur,  although  the  blood  itself  circulating  in  the  medulla  con- 
tains abundance  of  oxygen. 

In  the  case  of  carbonic-oxide  poisoning  the  blood  cannot  take 
up  oxygen  from  the  lungs,  although  there  is  abundance  of  oxygen 
present ;  and  in  a  similar  way  the  nerve-cells  of  the  medulla  may 
possibly  be  rendered  by  certain  drugs  unable  to  take  up  oxygen 
from  the  blood  circulating  through  the  medulla. 

In  simple  suffocation  the  internal  respiration  of  the  nerve- 
cells  in  the  medulla  is  arrested  by  the  general  venous  condition  of 
the  blood ;  in  carbonic-oxide  poisoning  by  the  oxygen  being  absent 


240  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

from  the  haemoglobin ;  in  nitrite  poisoning  by  the  oxygen  being 
locked  up  in  methasinoglobin.  In  all  those  cases  the  condition  of 
the  blood  is  betrayed  to  the  eye  by  the  appearance  of  the  mucous 
membranes,  which  in  suffocation  and  in  nitrite  poisoning  become 
dark  and  livid,  and  in  carbonic-oxide  poisoning  of  a  cherry-red 
colour.  Perhaps  the  change  is  most  conveniently  seen  in  the 
comb  of  a  cock  poisoned  by  these  substances ;  in  it  the  altera- 
tion in  the  colour  of  the  blood  produced  by  artificial  respiration  is 
readily  observed.  The  dependence  of  convulsions  upon  the  blood, 
is  also  easily  observed  :  the  convulsions  appearing  as  the  comb 
becomes  livid,  and  again  disappearing  when  artificial  respiration 
has  been  employed,  and  the  colour  of  the  comb  becomes  bright. 
In  poisoning  by  hydrocyanic  acid,  however,  I  have  observed  that 
convulsions  come  on  while  the  mucous  membranes  are  still  of  a 
bright  colour,  so  that  we  may  conclude  that  they  are  not  due  to 
a  venous  condition  of  the  blood,  as  in  ordinary  suffocation.  They 
might  be  due  to  the  formation  of  a  compound  between  the  hydro- 
cyanic acid  and  the  blood,  as  in  poisoning  by  nitrites  or  carbonic 
oxide ;  but  accurate  analyses  have  shown  that  hydrocyanic  acid 
does  not  displace  the  oxygen  in  haemoglobin  like  carbonic  acid; 
nor  lock  it  up  in  the  form  of  methsemoglobin  like  the  nitrites. 
We  are  therefore  obliged  to  consider  the  possibility  that  the 
dyspnoea  and  convulsions  produced  by  hydrocyanic  acid  are  not 
due  so  much  to  its  effect  upon  the  blood  circulating  in  the 
medulla  as  to  an  action  on  the  cells  of  the  medulla  itself,  by 
which  it  prevents  the  ordinary  internal  respiration  taking  place 
in  them. 

Action  of  Drugs  on  the  Respiratory  Centre. 

A  useful  method  of  testing  the  action  of  the  drug  itself  on  the  respiratory 
centre  is  to  perform  artificial  respiration  vigorously  so  as  to  produce  apnoea, 
to  allow  the  respiration  to  become  normal  again,  then  to  inject  the  drug  and 
again  try  to  produce  apncea.  If  the  drug  has  excited  the  respiratory  centre, 
apnoea  ■will  be  much  more  difficult  to  produce  after  its  injection  than  before, 
and  will  last  a  shorter  time  ;  if  it  has  depressed  it,  apnoea  will  be  more  easily 
produced,  and  will  last  longer. 

Apnoea  lasting  for  a  short  time  may  be  readily  produced  by  taking  five  or 
six  very  deep  breaths,  and  the  effect  of  drugs  on  the  respiratory  centre  may 
be  readily  tried  by  anyone  in  the  following  way.  Laying  a  watch  before 
him,  shutting  his  mouth  and  holding  his  nose,  let  him  first  ascertain  how 
many  seconds  he  can  hold  his  breath  after  previous  ordinary  respiration. 
Next  let  him  produce  a  certain  amount  of  apnosa  by  six  or  more  deep  respira- 
tions, and  again  ascertain  how  long  he  can  hold  his  breath.  After  repeating 
these  observations  several  times,,  let  him  take  the  drug  to  be  tested  and 
repeat  them  again,  taking  care  that  all  the  circumstances  should  be  the  same 
as  before. 

The  activity  of  the  respiratory  centre  is  augmented  by 
heat,  so  that  the  respirations  become  both  quicker  and  deeper, 
and  more  respiratory  work  is  done.  Strychnine,  ammonia, 
atropine,  duboisine,   brucine,  thebaine,  apomorphine,  emetine,, 


ghap.  x.]     ACTION  OF  DRUGS  ON  EESPIRATION.  241 

members  of  the  digitalis  group,  salts  of  zinc  and  copper,  have  a 
similar  action. 

It  appears  to  be  first  excited  and  then  depressed  by  caffeine, 
colchicin,  nicotine,  quinine,  and  saponine. 

It  is  diminished  by  cold,  so  that  the  respirations  become 
slow  and  shallow.  Chloral,  chloroform,  ether,  alcohol,  opium, 
pbysostigrnine,  muscarine,  gelsemine,  aconite,  and  veratrine  in 
large  doses,  all  have  a  similar  action. 

The  action  of  drugs  on  the  respiratory  centre  is  one  of  great 
importance,  not  only  as  giving  us  a  definite  basis  on  which  to 
found  a  plan  of  treatment  in  respiratory  diseases,  but  as  helping 
us  to  preserve  life  in  cases  of  poisoning — drugs  which  stimulate 
being  antagonised  by  those  which  depress  the  respiratory  centre, 
and  vice  versa. 

The  chief  afferent  nerves,  by  which  the  distribution  of  the 
respiratory  movements  is  altered,  may  be  divided  into  two  classes 
— those  having  an  inspiratory  and  those  having  an  expiratory 
action. 

The  expiratory  are  the  nasal  branches  of  the  fifth,  the  supe- 
rior laryngeal,  the  inferior  laryngeal,  and  the  cutaneous  nerves, 
especially  of  the  breast  and  belly. 

The  chief  inspiratory  are  the  branches  of  the  vagus. going  to 
the  lung,  but  all  sensory  nerves  when  slightly  stimulated  appear 
also  to  have  an  inspiratory  action. 

The  vagus  appears,  however,  to  contain  both  expiratory  and 
inspiratory  fibres,  which  are  alternately  stimulated  by  the  con- 
dition of  the  lung.  Expansion  of  the  lung  appears  to  stimulate 
mechanically  the  inhibitory  or  expiratory  fibres;  while  its  collapse 
stimulates  the  accelerating  or  inspiratory  fibres. 

When  the  expiratory  nerves  are  stimulated,  the  respiratory 
movements  become  slower  and  deeper ;  and  if  the  stimulation  be 
strong  they  may  stop  altogether  in  expiration,  with  the  diaphragm 
in  complete  relaxation. 

Stimulation  of  the  inspiratory  nerves  causes  the  respiration 
to  become  quicker  and  shallower,  and  at  length  to  stop  in 
inspiration,  the  diaphragm  being  in  a  state  of  tetanic  contraction. 

These  are  the  general  results,  but  they  are  not  quite  con- 
stant. The  reason  for  this  inconstancy  may  be  either  that  all 
the  nerves  contain  both  inspiratory  and  expiratory  fibres,  or  that 
the  same  fibres  may  stimulate  either  the  inspiratory  or  expiratory 
centres,  according  to  the  strength  of  the  stimulus  and  the  con- 
dition of  the  animal.  Thus,  when  the  vagus  is  divided,  the 
stimulus  which  is  conveyed  to  the  respiratory  centre  being  re- 
moved, the  respirations  usually  become  very  slow;  when  the 
central  end  of  the  divided  nerve  is  irritated  they  become  quick, 
and  a  very  strong  current  may  stop  them  in  inspiration.  But  this 
is  not  always  so  :  when  the  nerve  is  very  much  exhausted,  irri- 
tation by  a  strong  current  may  have  an  entirely  opposite  effect, 


242 


PHAEMACOLOGY  AND  THERAPEUTICS,      [sect,  u 


and  cause  the  respiration  to  stop  in  expiration  instead  of  inspira- 
tion. 

The  probability  that  the  same  nervous  fibres  may,  under  dif- 
ferent conditions,  excite  either  inspiration,  expiration,  or  the 
two  alternately,  is  rendered  still  greater  when  we  consider  some 
other  experiments ;  and  the  contradictory  results  which  have  been 
obtained  by  various  observers  in  regard  to  the  action  of  druga 
may  depend  to  a  great  extent  on  the  strength  of  the  stimulus 
they  have  used  and  the  state  of  exhaustion  of  the  animal.  Thus 
Langendorf  has  found  that  all  sensory  nerves  in  the  body  when 
slightly  stimulated  have  an  inspiratory,  but  when  stimulated 
more  strongly  have  an  expiratory  action.  Eosenthal  found  that 
irritation  of  the  crural  nerves  caused  alternately  deep  inspiration 
and  expiration  in  animals  which  were  not  narcotised.  In  nar- 
cotised animals,  Langendorf,  on  slight  irritation,  observed  an 
inspiratory  effect,  indicated  by  quickening  of  the  respiration  or 
slight  inspiratory  tetanus ;  but  when  the  experiment  was  con- 
tinued long,  or  the  irritation  was  increased,  the  contrary  or 
expiratory  effect  was  observed,  indicated  by  a  slowing  of  the  re- 
spiration. 

On  the  hypothesis  that  the  various  actions  of  respiration 
depend  upon  individual  centres,  inspiratory,  expiratory,  and  in- 


Inspiratory  and  Expiratory  Fibres) 
for  voluntas  alterations  in  Hespi-  \ 
ration J) 


Cutaneous  Nerves  of  Pace 

■g      ("Nasal  Branch  of  Fifth  Nerve..! 


Superior  Laryngeal  Nerve  . . .. 
Inferior  Laryngeal  Nerve 
Larynx ...*.••■.. 


b      (.Cutaneous  Nerves  of  the  Chest 

Expiratory  Fibres  of  Vagus  excited  by 
distension  of  Lung 


Inspiratory  Fibres  of  Vagus  excited  by 
collapse  of  Lung 


Respiratory  Centre  In 
Medulla  and  Cord 


Spinal  cord 


Fig.  81.— Diagram  showing  the  position  of  the  respiratory  centre,  and  the  afferent  nerves  which 
influence  it.    Inspiratory  nerves  are  indicated  by  plain,  aud  expiratory  by  dotted,  lines. 

hibitory,  it  is  exceedingly  difficult,  or  impossible,  to  understand 
the  contradictory  results  of  various  experimenters ;  but  the  ques- 
tion seems  much  less  intricate  when  we  regard  it  as  due  to  the 


chap,  x.]     ACTION  OP  DRUGS  ON  RESPIRATION. 


243 


interference  of  stimuli  passing  at  different  rates  in  different 
directions,  or  to  different  distances,  according  to  the  strength  of 
the  stimulus  and  the  irritability  or  exhaustion  of  the  nervous 
system. 

In  regard  then  to  inhibitory  or  slowing,  and  to  stimulating  or 
accelerating  nerves  or  fibres,  it  must  be  carefully  borne  in  mind 
that  the  same  fibres  may  possibly  have  either  the  one  or  the  other 
action,  according  to  the  conditions  under  which  they  are  acting. 

If  we  keep  this  carefully  in  view  we  may  continue  to  use  the 
terms  accelerating  and  slowing  or  inspiratory  and  expiratory 
nerves  as  convenient  means  of  expression.  These  are  shown 
in  the  accompanying  diagram  (Fig.  81). 

The  movements  of  respiration  are  most  easily  counted,  and  their  depth 
and  the  relation  of  inspiration  to  expiration  are  best  noted  by  causing 
them  to  register  themselves  on  a  revolving  cylinder.  Various  means  of 
doing  this  have  been  suggested  by  different  authors.  One  of  the  simplest 
consists  of  a  needle  pushed  into  the  diaphragm,  and  connected  by  a 
thread  with  one  of  Marey's  levers.  Marey's  pneumograph  consists  of  a 
cylinder  of  soft  indiarubber,  enclosing  a  spiral  spring,  whose  extremities 
are  connected  with  two  pieces  of  metal  which  form  the  ends  of  the 
cylinder.  A  band  is  passed  round  the  thorax  of  the  animal,  and  attached 
to  the  ends  of  the  cylinder.  The  interior  of  the  cylinder  is  brought  into 
communication  with  one  of  Marey's  levers,  and  as  each  respiratory  move- 
ment draws  the  ends  of  the  cylinders  wider  apart,  or  allows  them  to  approach, 
the  air  is  rarefied  or  compressed,  and  a  corresponding  movement  is  trans- 
mitted to  the  lever.  Bert  has  modified  this,  and  made  it  more  sensitive  by 
making  the  cylinder  itself  of  metal,  and  its  ends  of  indiarubber.  Another 
method — one  more  ordinarily  employed — is  to  introduce  one  limb  of  a 
T-tube  into  the  nostril  or  trachea  of  an  animal,  or  connect  it  with  a  tracheal 
cannula.  The  respired  air  passes  through  the  other  end,  and  the  third  limb 
is  connected  with  one  of  Marey's  levers. 

In  the  attempt  to  find  out  whether  the  alteration  in  respira- 
tion produced  by  any  drug  is  due  to  its  action  on  the  respiratory 
centre,  or  on  some  of  the  nerves  which  influence  it,  we  may 
find  the  following  table  useful  by  showing  at  a  glance  the  chief 
ways  in  which  the  respirations  may  be  rendered  quicker  or 
slower : — 


{Excitement  of  nerves. 
Greater  excitement  of 
respiratory  centre, 


Stimulation  of  the  vagus. 
Stimulation  of  optic  nerve. 
Stimulation  of  acoustic  nerve. 
Action  of  brain  (voluntary). 
Increased  temperature  of  blood. 
Increased  venosity  of  blood. 
Action  of  drugs. 


Diminished       excite-  f  Diminished  venosity  of  blood. 


The  respiratory 
movements  may< 
be  rendered  slow 
by 


ment  of  respiratory 
centre. 


Nervous  influences. 


Action  of  drugs. 
,  Action  of  brain  (voluntary), 
f  Paralysis  of  vagi. 

Stimulation  of  superior  laryngeal  nerves. 

Stimulation  of  inferior  laryngeal  nerves. 

Stimulation  of  nasal  nerves. 

Stimulation  of  cutaneous  nerves. 
iStimulation  of  splanchnic  nerves. 

r  2 


244  PHAEMACOLOGY  AND  THERAPEUTICS.,    [sect.  r. 

If  the  drug  to  be  experimented  on  be  injected  subcutaneously 
or  into  the  veins,  the  actions  on  the  respiratory  centre  and  on 
the  vagi  are  the  chief  points  which  require  attention ;  but  if  we 
are  experimenting  with  a  vapour,  its  local  action  on  the  nasal,, 
laryngeal,  and  possibly,  also,  on  the  pharyngeal  nerves  '  must  be 
carefully  attended  to,  as  it  may  greatly  modify  its  general  action 
on  the  respiratory  centres.  Thus  Kratschmer  has  found  that 
tobacco-smoke  inhaled  by  a  rabbit  through  its  nostrils,  or  blown 
upward  into  the  nasal  cavity  from  an  aperture  in  the  trachea, 
will  cause  arrest  of  breathing  in  a  state  of  expiration  from  the 
irritating  effect  of  the  vapour  of  the  nasal  branches  of  the  fifth, 
while  it  has  no  such  effect  when  blown  into  the  lungs.  Ammonia, 
when  inhaled,  also  arrests  the  respiratory  movements  in  the 
same  way ;  but  Knoll 2  has  observed  that  if  it  be  blown  into  the 
lungs  while  the  nostrils  are  carefully  protected  from  its  influence, 
it  causes  accelerated  and  shallow  breathing,  alternating  with  slow 
and  deep  respirations,  and  occasional  stoppages  in  the  position 
of  expiration,  obviously  from  its  action  on  the  different  fibres  of 
the  vagi. 


Action  of  Drugs  on  the  Respiratory  Nerves. 

In  experiments  regarding  the  effect  of  drugs  upon  the  re- 
spiration, the  voluntary  influence  of  the  brain  is  excluded  by  the 
use  of  ether,  chloroform,  opium,  or  chloral,  or  by  section  of  the 
crura  cerebri.  In  the  case  of  such  poisons  as  cause  sickness 
allowance  must  be  made  for  the  effect  of  gastric  irritation.  It 
will  usually  be  found  that  before  vomiting  occurs  the  respiratory 
movements  are  very  rapid,  but  they  become  slower  after  vomiting 
has  taken  place.  As  the  chief  afferent  fibres  from  the  stomach 
are  contained  in  the  vagus,  the  effect  of  irritation  of  the  gastric, 
as  well  as  of  other  fibres  contained  in  these  nerves,  is  prevented 
by  their  division.  Sometimes  the  action  of  a  drug  on  the 
peripheral  ends  of  the  vagus  and  upon  its  roots  in  the  medulla 
may  produce  exactly  opposite  effects  upon  the  respiration.  Thus 
atropine  appears  to  lessen  the  excitability  of  the  respiratory 
fibres  of  the  vagus,  while  it  stimulates  the  respiratory  centre. 
Such  an  action  may  be  to  a  certain  extent  inferred  from  the 
respiration  becoming  slower  almost  immediately  after  the  injec- 
tion of  the  drug  into  the  jugular  vein,  and  while  it  is  still  passing 
through  the  lungs,  and  by  this  slowing  being  quickly  succeeded 
by  acceleration  when  the  drug  begins  to  circulate  through  the 
medulla. 

There  are  two  kinds  of  experiment  by  which  such  a  conclu- 
sion may  be  tested.     The  one  is  to  apply  the  drug  first  to  the 


Brown-SSquarcl,  Archives  of  Scientific  and  Practical  Medicine,  p.  94. 
Sitzungsber.  der  Wien.  Acad.,  vol.  lxviii.  Abt.  3,  p.  255. 


chap,  x.]      ACTION  OF  DEUGS  ON  EESPIEATION.  245 

medulla  by  injecting  it  into  the  carotid  artery,  and  seeing  whether 
acceleration  occurs  at  once  and  afterwards  becomes  less  when 
the  drug  has  had  time  to  pass  round  again  to  the  lungs.  The 
other  way  is  to  divide  the  vagi  before  the  injection  and  observe 
the  effect.  Any  alteration  in  the  respiration  in  the  way  of  either 
quickening  or  slowing  which  the  drug  produced  in  the  uninjured 
animal  should  remain  the  same  after  division  of  the  vagi  if 
its  effect  were  due  to  its  action  on  the  medulla,  but  will  be 
absent  if  it  were  due  to  an  action  upon  the  peripheral  ends  of 
the  vagi. 

This  method  was  introduced  into  pharmacological  research 
by  Von  Bezold  in  his  admirable  research  on  atropine,  and  it  is 
the  one  usually  employed. 

There  is  one  fallacy,  however,  which  must  not  be  entirely  lost  sight  of, 
which  is,  that  after  division  of  the  vagi  the  nerves  which  remain  in  con- 
nection with  the  respiratory  centre  have  chiefly  a  slowing  action  on  the 
respiration;  and  thus  a  drug  which  really  renders  the  respiratory  centre 
more  susceptible  to  reflex  influences  might  seem  to  have  a  depressing  action 
upon  it. 

While  atropine  injected  into  the  jugular  vein  seems  to  pro- 
duce first  a  slowing  of  the  respiration,  due  to  its  paralysing 
action  on  the  vagus  ends,  and  afterwards  a  progressive  quickening 
as  more  of  it  is  carried  out  of  the  lungs  into  the  medulla,  phy- 
sostigmine,  muscarine,  and  veratrine  have  an  opposite  action, 
quickening  the  respiration  at  first  by  their  stimulating  action  on 
the  vagus  ends,  and  afterwards  slowing  it  by  their  action  on  the 
medulla. 

In  the  action  of  veratrine  upon  the  pulmonary  branches  of 
the  vagus  we  may  notice  a  resemblance  to  the  stimulant  action 
which,  as  already  mentioned,  it  exerts  upon  the  nerves  of  or- 
dinary sensation.  If  the  sensory  branches  of  the  vagus  are 
affected  by  drugs  in  a  somewhat  similar  way  to  those  of  ordinary 
sensation,  as  the  action  of  veratrine  might  lead  us  to  imagine, 
we  should  expect  them  to  be  much  stimulated  also  by  aconite, 
and,  indeed,  according  to  Boehm  and  Ewers,  this  is  the  case. 
The  respiratory  changes  produced  by  aconite  are  regarded  by 
them  as  due,  in  part,  to  irritation  of  the  peripheral  ends  of  the 
vagus,  and  disappear  on  section  of  the  vagi  or  the  administra- 
tion of  atropine. 

Sternutatories  or  Errhines. 

These  are  drugs  which  cause  sneezing  and  increased  secre- 
tion from  the  nose  when  locally  applied  to  it.  The  drugs  must 
be  in  a  pulverised  condition.     The  chief  are ; — 

Tobacco  (snuff).  Euphorbium. 

Veratrum  album.  Sassy  bark. 

Ipecacuanha.  Saponine. 


246  PHARMACOLOGY  AND  THERAPEUTICS,      [sect.  I. 

Irritation  applied  to  the  nose  is  transmitted  by  the  nasal 
branches  of  the  fifth  to  the  respiratory  centre  in  the  medulla 
oblongata,  and  excites  the  sudden  and  forcible  expiratory  move- 
ments of  sneezing.  At  the  same  time,  however,  the  stimulus  is 
transmitted  to  the  vaso-motor  centre,  and  the  blood-pressure 
becomes  considerably  increased  by  the  contraction  of  small  vessels 
throughout  the  body,  even  when  no  sneezing  occurs.  When 
sneezing  takes  place,  the  pressure  is  still  further  increased  by 
the  muscular  efforts  which  occur  in  the  act.  It  is  probable  that 
there  is  not  only  general  rise  in  blood-pressure  but  also  that 
local  dilatation  of  the  cerebral  vessels  is  reflexly  produced  by 
the  nasal  irritation,  and  thus  a  stimulant  effect  is  produced  on 
the  brain.  Snuff  is  therefore  employed  as  a  luxury  giving  a 
feeling  of  comfort  and  enabling  the  snuff-taker  to  think  more 
clearly — '  clearing  the  head  '  as  it  is  often  termed  (vide  p.  193). 

Uses. — Though  comparatively  little  used  now,  sternutatories 
were  formerly  employed  in  failure  of  memory,  deafness,  and 
severe  persistent  headache.  From  the  violent  expulsive  efforts 
which  they  induce,  they  were  given  also  to  cause  the  expulsion 
of  foreign  bodies  from  the  air-passages,  and  to  hasten  the  ex- 
pulsion of  the  child  in' cases  of  lingering  labour  where  no  ob- 
struction was  present,  but  where  expulsive  force  was  deficient. 
They  were  given  also  in  order  to  try  and  check  diseases  at  the 
commencement,  by  what  was  termed  '  shock  to  the  system.' 

One  curious  thing  is  to  be  remarked,  that  stimulation  of  one 
part  of  the  respiratory  tract  may  arrest  abnormal  actions  in 
another.  Thus  Marshall  Hall  has  shown  that  actual  sneezing 
may  frequently  be  prevented,  after  the  inspiration  by  which  it 
is  usually  preceded  has  occurred,  by  forcibly  rubbing  the  end  of 
the  nose  or  by  tightly  compressing  the  nostrils.  In  a  similar 
way  irritation  of  the  interior  of  the  nose  by  snuff  will  sometimes 
arrest  obstinate  hiccough. 

Contraindications. — On  account  of  the  high  blood-pressure 
which  they  produce  their  use  is  by  no  means  free  from  danger 
in  persons  affected  with  atheroma  or  a  tendency  to  pulmonary 
haemorrhage  or  apoplexy,  as  they  may  cause  rupture  of  a  vessel, 
and  in  those  who  suffer  from  hernia  or  from  prolapsus  of 
the  uterus,  they  may  seriously  increase  the  gravity  of  these 
affections. 


Respiratory  Sedatives. 

These  are  substances  which  diminish  cough  and  spasmodic 
difficulty  of  breathing. ' 

They  may  be  divided  into  drugs  which — 

(1)  Tend  to  remove  the  irritation  which  acts  as  the  exciting 
cause  of  the  cough. 


chap,  x.]     ACTION  OF  DRUGS  ON  RESPIRATION. 


247 


(2)  Tend  to  lessen  f  (a)  the  afferent  nerves  in  the  lungs ; 
irritability  of  |  (6)  the  respiratory  centre. 

Pathology  of  cough. — Cough  consists  in  a  deep  inspiration 
followed  by  a  forcible  expiration  with  closed  glottis,  so  that  the  air 
is  driven  rapidly  through  the  larynx,  carrying  with  it  foreign  sub- 
stances, liquid  or  solid,  which  may  be  present  in  the  air-passages. 
As  it  is  a  modified  respiratory  act,  the  nerve-centre  by  which  the 
muscles  employed  in  it  are  co-ordinated  is  situated  in  the  medulla 
oblongata. 

The  afferent  fibres  by  which  cough  may  be  excited  are  chiefly 
branches  of  the  vagus.    One  of  the  most  powerful  is  the  superior 


Pharynx  \  Cough  very  vio- 
I  lent.ofteuaccom- 
[  panied  by  retch- 

CEsophagus  j  ing  or  vomiting. 


Liver 


Fig.  82.— Diagram  of  the  afferent  nerves  by  which  cough  may  be  excited.  These  nerves  are  shown 
passing  to  the  respiratory  centre  in  the  following  order  from  above  downward— from  the  audi- 
tory meatus,  pharynx,  upper  part  of  oesophagus,  larynx  and  trachea,  bronchi,  lung,  costal 
pleura,  liver  and  spleen. 

laryngeal  nerve  distributed  to  the  glosso-epiglottidean  folds  and 
to  the  whole  of  the  interior  of  the  larynx,  and  this  being  a 
special  expiratory  nerve  we  find  that  irritation  of  the  larynx  and 
also  of  the  trachea  is  usually  characterised  by  a  cough  with  very 
violent  expulsive  efforts.  Irritation  of  the  mucous  membrane  of 
the  trachea  especially  at  the  bifurcation  of  the  bronchi,  and 
irritation  of  the  substance  of  the  lung,  also  give  rise  to  cough  ; 
and  irritation  of  the  costal  pleura  and  of  the  oesophagus  does  so 
also.1  Irritation  of  the  auditory  meatus  at  the  point  to  which 
the  auricular  branch  of  the  vagus  is  distributed  will  also  cause 
coughing ;  and  cough  appears  to  be  also  induced  by  irritation  of 
certain  parts  of  the  interior  of  the  nose.  These  are  the  surfaces 
of  the  inferior  and  middle  turbinated  bones,  the  most  sensitive 


Kohts,  Virchow's  Archiv,  66, 191. 


248  PHAEMACOLOGY  AND  THERAPEUTICS,      [sect.  & 

part  being  the  posterior  end  of  the  inferior  turbinated  bone  and 
the  portion  of  the  septum  immediately  opposite.1  The  sudden 
application  of  cold  to  the  skin  on  various  parts  of  the  body  will 
sometimes  cause  coughing.  Probably  the  cough  in  this  case  is 
not  due  to  the  stimulus  being  conveyed  directly  to  the  respiratory 
centre  by  the  cutaneous  nerves,  but  to  its  causing  congestion 
of  the  air-passages,  as  in  Eossbach's  experiments  (p.  252).  The 
congestion  then  causes  irritation  of  the  sensory  nerves  of  the 
bronchi,  and  occasions  cough. 

T  have  seen  irritation  of  the  liver  and  spleen,  induced  by 
percussion  over  them,  in  a  man  suffering  from  chronic  enlarge- 
ment due  to  malaria,  likewise  cause  coughing.2  In  addition  to 
those  nerves,  however,  it  appears  that  irritation  of  the  glosso- 
pharyngeal branches  distributed  to  the  pharynx,  where  the 
digestive  and  respiratory  tracts  coincide  as  they  cross  one  an- 
other, may  not  only  excite  coughing,  but  may  also  act  as  an 
auxiliary  to  irritation  of  the  branches  of  the  vagus.  The  com- 
bined action  of  the  two  may  thus  induce  cough,  when  irritation 
of  the  vagus  alone  would  not  do  so.  Thus  we  find  that  many 
persons  begin  to  cough  as  soon  as  they  lie  down,  but  that  some- 
times by  lying  round  partially  on  the  face,  the  cough  ceases.  In 
these  persons  the  uvula  is  often  found  to  be  long  and  much  con- 
gested, and  the  tickling  which  it  produces  as  it  rests  upon  the 
pbarynx  or  pillars  of  the  fauces  seems  to  aid  the  irritation  in 
the  respiratory  passages,  and  produce  cough. 

Cough  due  to  irritation  of  those  parts  of  the  respiratory 
tract  where  the  nerves  are  chiefly  expiratory,  as  the  pharynx, 
larynx,  trachea,  and  large  bronchi,  is  usually,  as  might  be  ex- 
pected, loud,  explosive,  and  prolonged ;  while  cough  due  to  irri- 
tation of  those  parts  where  the  nerves  are  chiefly  inspiratory  is 
short  and  hacking  (Pig.  82). 

Cough  produced  by  irritation  of  the  pharynx  where  the, re- 
spiratory and  digestive  passages  cross  one  another,  is  not  only 
violent,  noisy,  and  barking,  but,  as  we  would  naturally  expect, 
is  not  unfrequently  accompanied  by  retching  or  vomiting. 

Pharyngeal  irritation  may  accompany  dyspepsia,  and  it  is 
probably  the  origin  of  the  so-called  stomach-cough.  Irritation 
of  the  stomach  itself,  or  of  its  nerves,  causes  vomiting,  but  does 
not  produce  cough. 

Nevertheless  there  is  a  rationale  for  the  common  expression 
'  stomach-cough.'  In  some  experiments  on  the  reflex  origin  of 
cough,  E.  Meyer 3  has  noticed  that  when  some  part,  from  which 

1  On  Nasal  Cough,  by  John  N.  Mackenzie,  M.D.,  reprint  from  The  American 
Journal  of  the  Medical  Sciences,  July  1883. 

2  These  observations  were  made  in  January  and  April  1879,  but  not  published. 
Naunyn,  in  a  paper  published  in  the  Deutsch.  Archw  f.  Mm.  Med.  in  March  1879 
recorded  similar  observations. 

■  E.  Meyer,  Correspondenzblatt  d.  Schweiser  Aerate,  No.  1, 1876. 


chap,  x.]     ACTION  OP  DRUGS  ON  RESPIRATION.  249 

cough  can  be  reflexly  induced,  is  already  in  a  state  of  irritation, 
cough  can  be  brought  on  with  great  ease  by  irritation  of  a  neigh- 
bouring part  which  would  not  by  itself  cause  cough.  Something 
of  this  kind  appears  to  occur  with  the  stomach,  for  although 
irritation  of  the  stomach  alone  will  not  cause  coughing,  yet  it 
will  do  so  if  irritation  of  the  larynx  and  trachea  are  already 
present.  Thus  I  have  observed  violent  spasms  of  coughing  occur, 
along  with  acidity  and  heartburn,  some  time  after  a  meal,  in  a 
person  suffering  from  congestion  of  the  pharynx,  larynx,  or 
trachea.  The  connection  between  the  cough  and  the  acidity  was 
shown  by  the  cough  ceasing  as  soon  as  the  acidity  was  relieved 
by  a  dose  of  alkali  and  the  consequent  removal  of  the  irritation 
to  the  stomach,  which  the  acidity  had  produced. 

Remedies  which  Lessen  Irritation. 

Soothing  remedies  applied  to  the  pharynx  greatly  relieve 
cough,  although  they  do  not  reach  so  far  down  as  the  epiglottis. 
Mucilaginous  remedies  are  very  useful  for  this  purpose,  and  they 
may  either  be  employed  alone  or  as  vehicles  for  the  local  appli- 
cation of  sedatives  such  as  morphine.  Thus,  a  piece  of  extract 
of  liquorice  allowed  to  dissolve  in  the  mouth,  a  marsh-mallow 
lozenge,  a  gum-jujube,  or  a  sip  of  linseed-tea,  by  covering  the 
back  of  the  throat  with  a  mucilaginous  coating,  will  lessen  cough 
to  a  great  extent.  Such  remedies  are  especially  useful  where  the 
cough  depends  on  congestion  of  the  pharynx  and  trachea.  '>  In 
such  cases  no  abnormal  sound  at  all  may  be  heard  in  ausculta- 
tion, and  the  cough  being  due  to  irritation  of  the  parts  supplied 
by  the  superior  laryngeal  nerve,  has  a  peculiarly  convulsive 
expiratory  character  often  termed  '  barking.' 

Other  remedies  lessen  cough  by  diminishing  congestion  of 
the  respiratory  passages,  and  thus  lessening  the  irritation  which 
causes  the  cough.  Many  of  these  also,  however,  come  under  the 
class  of  expectorants  (p.  250),  inasmuch  as  the  diminished 
congestion  is  frequently  associated  with  increase  of  the  ex- 
pectoration. Others,  again,  although  they  diminish  cough,  are 
included  rather  under  the  head  of  '  cardiac  tonics,'  or  sedatives. 
Digitalis  is  an  example  of  this.  In  the  congestion  due  to 
cardiac  disease,  and  even  in  that  due  to  bronchitis,  digitalis,  by 
strengthening  the  heart  and  by  contracting  the  vessels,  may 
lessen  the  congestion  in  the  lungs,  and  give  the  patient  relief. 
Squill  and  a  number  of  other  drugs  have  an  action  on  the  blood- 
vessels similar  to  that  of  digitalis. 

Other  remedies,  such  as  the  vapour  of  hydrocyanic  acid, 
conium,  stramonium,  and  tobacco,  have  a  local  sedative  action 
on  the  lung,  and  may  lessen  cough ;  they  also  are  used  in  order- 
to  diminish  local  spasm  of  the  bronchioles,  and  thus  to  relieve 
spasmodic  asthma. 


250  PHABMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 


Pulmonary  Sedatives. 

These  are  remedies  which  lessen  the  irritability  of  the  respira- 
tory centre  or  of  the  nerves  connected  with  it.  The  chief  drugs 
which  diminish  the  excitability  of  the  respiratory  centre  are 
opium  and  its  principal  alkaloid,  morphine.  Morphine  and 
opium  have  a  double  action  in  lessening  cough :  they  not  only 
lessen  the  excitability  of  the  respiratory  centre,  but  they 
diminish  the  secretion  of  mucus  in  the  bronchial  tubes,  and 
probably  thus  also  lessen  the  irritation.  Hydrocyanic  acid  has 
also  a  sedative  action  on  it,  but  it  is  by  no  means  so  powerful  as 
the  others. 

Belladonna  and  stramonium  have  a  rather  peculiar  action, 
stimulating  the  respiratory  centre,  and  at  the  same  time  appear- 
ing to  lessen  the  excitability  of  the  ends  of  the  vagi  in  the  lungs. 
Atropine  has  but  a  very  slight  and  uncertain  action  on  the 
respiratory  centre  in  preventing  cough,  if  indeed  it  has  any  at 
all.  It  has,  however,  a  powerful  effect — much  more  powerful 
than  that  of  opium, — in  completely  arresting  the  secretion 
from  the  bronchial  tubes.  The  cases  in  which  it  is  useful  are 
therefore  those  where  the  cough  depends  upon  excessive  secre- 
tion; In  cases  where  the  mucous  membrane  is  already  too  dry, 
it  would  be  injurious  rather  than  beneficial. 

When  apomorphine  and  morphine  are  given  together  they  do 
not  destroy  each  other's  action,  so  that  from  the  combination  we 
get  increased  secretion  from  the  mucous  membrane,  with  dimin- 
ished irritability  of  the  respiratory  centre,  and  consequently 
lessened  cough.  The  cases  in  which  this  combination,  then,  is 
useful,  are  those  where  there  is  difficulty  of  breathing,  continual 
cough,  and  thick  tenacious  mucus.  When  morphine  and  atropine 
are  given  together,  also,  they  do  not  destroy  each  other's  action ; 
and  thus  dryness  of  the  mucous  membrane  is  produced,  along 
with  diminished  irritability  of  the  centre  for  coughing.  This 
combination  is  therefore  useful  in  cases  of  catarrh,  emphysema, 
and  phthisis,  where  there  is  copious  secretion  of  mucus.  In 
phthisis  it  is  especially  indicated  on  account  of  the  beneficial 
action  of  atropine  in  also  lessening  sweating.  Where  the  copious 
expectoration  depends  upon  the  presence  of  a  cavity,  and  not  on 
excessive  secretion  from  the  bronchi,  it  will  not  be  much  affected 
by  the  use  of  these  remedies. 

Expectorants. 

Expectorants  are  remedies  which  facilitate  the  removal  of 
secretions  from  the  air-passages.  The  secretion  may  be  ren- 
dered more  easy  of  removal,  either  by  an  alteration  in  its 
character  rendering  it  less  adhesive  and  more  easily  detached 


chap,  x.]     ACTION  OF  DEUGS  ON  EESPIEATION.  251 

from  the  air-passages,  or  by  increased  activity  of  the  expulsive 
mechanism. 

Our  knowledge  of  the  use  of  expectorants  is  founded  chiefly 
on  empiricism.  We  are  almost  entirely  indebted  to  the  recent 
experiments  of  Eossbach  for  any  precise  information  as  to  their 
mode  of  action.1 

The  secretion  from  the  air-passages,  like  other  secretions, 
depends  partly  upon  the  condition  of  the  circulation,  and  partly 
on  the  secreting  cells  themselves. 

•  In  healthy  conditions  the  increased  secretion  and  increased 
circulation  of  blood  in  the  mucous  membrane  go  together,  but 
just  as  in  the  case  of  the  sweat-glands,  these  two  factors  may 
occur  independently  of  each  other,  and  secretion  may  take  place 
rapidly  when  the  circulation  is  diminished  and  the  mucous  mem- 
brane is  anaemic,  and,  on  the  other  hand,  it  may  stop  altogether 
when  the  vessels  are  dilated  and  the  mucous  membrane  is  con- 
gested. The  latter  happens  both  in  cases  of  disease  and  in 
animals  poisoned  by  atropine. 

The  secretion  from  the  normal  respiratory  mucous  membrane 
consists  of  a  thin  solution  of  mucin  which  dries  very  slowly,  and 
is  only  secreted  in  sufficient  quantity  to  keep  the  mucous  mem- 
brane moist.  It  is  slightly  adhesive,  and  any  particles  of  dust, 
&c,  which  may  have  found  their  way  into  the  trachea,  will  stick 
to  the  walls  of  the  air-passages,  and  will  be  gradually  moved  up 
towards  the  mouth  by  the  cilia  with  which  the  cells  of  the  mucous 
membrane  are  furnished.  Any  excess  of  mucus  secreted  in 
consequence  of  irritation  will  also  be  moved  upwards  by  the  cilia 
in  a  similar  manner.  In  the  ciliated  cells  of  the  mucous  mem- 
brane we  recognise  a  structure  which  is  frequently  met  with  in 
animals  lower  down  the  scale  of  existence,  and  the  mucous  mem- 
brane of  the  respiratory  passages  appears  to  resemble  the  parts 
of  lower  organisms,  in  being  very  slightly  controlled  by  the 
central  nervous  system.  When  not  irritated  it  secretes  slowly 
and  regularly ;  when  irritated  locally  the  secretion  is  increased, 
but  irritation  of  the  nerves  passing  to  it,  such  as  the  vagus,  the 
superior  or  inferior  laryngeal,  or  the  sympathetic,  does  not  cause 
any  increase  as  it  does  in  the  case  of  the  submaxillary  gland. 
These  nerves,  however,  can  influence  it  indirectly  through  the 
circulation,  for  when  they  are  divided  an  increased  dilatation 
of  the  vessels  occurs  in  the  mucous  membrane  of  the  trachea,  a 
freer  circulation  of  blood  occurs,  and  increased  secretion  is  thus 
indirectly  produced.  When  they  are  irritated,  however,  and 
anaemia  of  the  trachea  produced,  the  secretion  is  not  arrested* 
but  continues. 

The  circulation  in  the  mucous  membrane  is  readily  affected 
reflexly  by  irritation  of  other  parts  of  the  body.    When,  for 

1  Festschrift  der  Julius-Maximilian-  Universitat  eu  Wiirzburg,  Leipzig. 


252  PHAEMACOLOGY  AND  THEEAPEUTICS.     [bect.  i. 

example,  a  warm  poultice  is  laid  for  five  or  ten  minutes  on  the  - 
belly  of  an  animal,  and  then  afterwards  replaced  by  ice,  the 
mucous  membrane  of  the  trachea  and  larynx  becomes  m  halt  a 
minute  deadly  pale  from  the  contraction  of  its  vessels.  Though 
the  ice  is  still  allowed  to  remain  on  the  belly,  the  tracheal  mucous 
membrane  quickly  changes  colour,  and  to  the  paleness  succeeds 
first  slight  redness,  then  deep  red  congestion,  and  m  five  or  ten 
minutes  lividity.  This  lividity  shows  that  the  congestion  is  not 
arterial  but  venous,  and  that  the  circulation,  instead  of  being 
quicker  is  really  slower.  Along  with  the  increase  of  congestion 
in  the  mucous  membrane,  the  amount  of  mucus  secreted  in- 
creases. When  the  ice  is  removed  for  half  an  hour,  and  again 
replaced  by  the  warm  poultice,  the  bluish-red  colour  of  the 
mucous  membrane  almost  immediately  disappears  and  gives  place 
to  a  rosy  colour  which  is,  however,  redder  than  normal.  Ice 
again  applied  will  cause  a  second  contraction  of  the  vessels  and 
paleness,  though  much  less  than  before.  These  experiments 
show  how  sensitive  is  the  mucous  membrane  of  the  trachea  to 
reflex  stimulation  of  other  parts  of  the  body  by  heat  or  cold,  and 
enable  us  to  understand  more  readily  how  a  draught  of  cold  air 
on  some  part  of  the  body  should  cause  inflammation  of  the 
respiratory  organs.  » 

Action  of  Drugs  on  the  Secretion.— Alkalies,  such  as  car- 
bonate of  sodium,  injected  into  the  blood,  lessen,  or  in  large 
quantity  completely  arrest,  the  secretion  of  mucus  from  the 
trachea. 

This  experimental  result  is  in  contradiction  to  the  teaching 
of  clinical  experience,  which  shows  us  that  alkalies  increase  the 
amount  of  secretion,  and  render  it  more  fluid.  The  results  of 
clinical  observation  are  quite  as  certain  as  those  of  Eossbach's 
experiments,  for  we  may  not  only  remark  the  greater  quantity  of 
expectoration,  and  its  greater  fluidity  in  persons  taking  alkalies, 
but  we  may  note  the  alteration  which  they  occasion  in  the 
amount  and  nature  of  the  moist  rales  heard  within  the  lungs. 
This  can  be  observed  most  readily  in  persons  suffering  from 
phthisis,  especially  round  the  margin  of  the  cavity.  After  catch- 
ing a  slight  cold  an  extension  of  consolidation  may  be  remarked, 
in  which  moist  rales  readily  occur  on  the  administration  of  dilute 
alkalies.  When  these  are  continued  until  the  expectoration  has 
been  free  for  a  day  or  two  and  the  rales  diminish,  acids  may  be 
given  with  advantage,  so  as  to  dry  up  the  expectoration  still 
more.  But  if  the  acid  is  given  too  soon  the  expectoration  dimi- 
nishes, but  the  cough  increases  and  becomes  troublesome  to  the 
patient. 

In  all  probability  the  difference  between  the  results  of  clinical 
observation  and  Eossbach's  experiments  depends  upon  the  dif- 
ference of  dose,  the  quantity  usually  given  to  a  patient  being 
proportionately  much  smaller  than  that  which  he  employed.    We 


chap,  x.]      ACTION  OP  DEUGS  ON  EESPIEATION.  253 

are  able  to  observe  a  similar  difference  between  tbe  effects  of 
small  and  large  doses  in  the  case  of  iodide  of  potassium ;  a  small 
dose  of  a  grain  and  a  half,  taken  by  a  healthy  man  three  times 
a  day,  will  almost  certainly  cause  the  nose  to  run  freely,  while  if 
the  dose  be  increased  to  ten,  twenty,  or  thirty  grains  the  .excessive 
secretion  will  almost  certainly  be  arrested. 

The  local  application  of  one  to  two  per  cent,  solution  of 
sodium  carbonate  has  very  little  action.  The  local  application  of 
strong  liquor  ammoniee  causes  both  congestion  and  increased 
secretion  of  mucus.  Very  strong  solutions  cause  a  croupous 
exudation  from  the  surface  of  the  mucous  membrane.  The  local 
application  of  dilute  acetic  acid  (three  per  cent,  solution)  has  a 
similar  action  to  weak  solutions  of  ammonia  :  the  mucous  mem- 
brane becoming  redder  and  secreting  more  mucus. 

When  acetic  acid  was  given  internally,  Eossbach  observed  in 
one  case  that  the  mucus,  which  was  before  watery  and  clear, 
became  gelatinous  and  opalescent.  This  result  agrees  with  what 
one  finds  clinically,  that  acids  dry  up  the  secretion  and  make  it 
harder  to  expectorate. 

Among  astringents  Eossbach  tried  tannin,  alum,  and  nitrate 
of  silver;  the  first  two" when  locally  applied  made  the  mucous 
membrane  appear  paler  by  altering  the  epithelium  and  rendering 
it  opaque,  so  that  the  vessels  underneath  could  hardly  be  seen  ; 
at  the  same  time  they  arrested  the  secretion  of  mucus  almost 
entirely.  A  four  per  cent,  solution  of  nitrate  of  silver  also  caused 
opacity  of  the  epithelium,  arrest  of  secretion,  and  dryness  of  the 
mucous  membrane.  There  appears  to  be  a  difference  in  the 
action  of  nitrate  of  silver  on  the  mucous  membrane  of  the  nose 
and  on  the  trachea,  as  when  the  inside  of  the  nose  is  touched 
by  it,  it  causes  a  profuse  secretion,  whereas  it  causes  dryness  in 
the  trachea. 

The  vapour  of  oil  of  turpentine  mixed  with  air  arrests  the 
secretion  of  mucus,  whilst  a  current  of  air  alone,  without  admix- 
ture with  oil  of  turpentine,  will  act  as  an  irritant  to  the  mucous 
membrane  and  increase  secretion.  Here  again,  however,  a 
marked  difference  is  to  be  seen  in  the  effect  of  small  and  large 
doses,  for  when  a  watery  solution  containing  from  one  to  two 
per  cent,  of  oil  of  turpentine  was  dropped  directly  on  the  mucous 
membrane,  it  became  less  vascular,  but  the  secretion  was  at 
once  increased,  instead  of  being  diminished,  as  it  was  by  the 
vapour. 

This  action  of  oil  of  turpentine  is  of  great  cherapeutical 
importance,  inasmuch  as  in  many  cases  of  bronchitis  we  have 
profuse  secretion  with  vascular  congestion,  a  condition  likely  to 
be  removed  by  the  vapour  of  oil  of  turpentine. 

Apomorphine,  emetine,  and  pilocarpine,  when  given  internally, 
all  cause  a;  great  increase  of  the  secretion  of  mucus,  but  they 
do  not  alter  the  vascularity  of  the  mucous  membrane.     The., 


254  PHARMACOLOGY  AND  THERAPEUTICS,     [sect.  i. 

most  powerful  of  all  these  is  pilocarpine,  and  after  it  come  apo^ 
morphine  and  emetine.  One  would  therefore  expect  that  pilo- 
carpine would  be  the  best  remedy  in  catarrhal  conditions,  but 
this  is  not  the  case,  for  its  other  actions  on  the  salivary  and 
sweat  glands  and  on  the  heart  render  its^  administration  un- 
pleasant for  the  patient.  Sometimes  also  hi  children  oedema  of 
the  lungs  has  followed  its  use.  Apomorphine,  on  the  contrary, 
has  been  found  by  Rossbach  to  be  of  the  greatest  service  in 
catarrh  of  the  larynx,  trachea,  and  bronchi,  both  in  adults  and 
in  children.  Ipecacuanha  has  long  been  recognised  as  one  of  the 
most  useful  expectorants,  but  the  dose  given  is  often  too  small. 

Rossbach's  experiments  have  shown  that  the  consequence  of 
sudden  changes  of  heat  and  cold  applied  to  a  part  of  the  body  is 
congestion  of  the  respiratory  mucous  membrane  with  diminished. 
circulation  and  stagnation  of  blood  in  the  veins.  A  similar  con- 
dition occurs  in  many  cases  of  chronic  bronchitis,  and  in  them 
we  not  unfrequently  find  great  benefit  from  vascular  tonics  such 
as  digitalis,  which,  in  addition  to  stimulating  the  vaso-motor 
centre,  increase  the  activity  of  the  heart,  and  thus  tend  to  main- 
tain the  pulmonary  circulation. 

In  what  way  cod-liver  oil  affects  the  bronchial  mucous  mem- 
brane it  is  perhaps  hard  to  say,  but  there  is  no  doubt  whatever 
that  it  is  one  of  the  most  efficient  expectorants  that  we  possess, 
and  in  cases  of  chronic  bronchitis  it  affords  more  relief  than 
any  of  the  ordinary  expectorants.  It  is  possible  that,  being  a 
form  of  fat  which  is  readily  assimilated,  it  is  taken  up  by  the 
young  epithelial  cells  of  the  respiratory  mucous  membrane,  and 
thus  enables  them  to  grow  and  maintain  their  attachment  to  the 
mucous  membrane,  instead  of  being  at  once  shed  in  an  unde- 
veloped form  as  pus-cells  in  the  expectoration. 

Action  of  Drugs  on  the  Expulsive  Mechanism.— The 
expectorants  which  act  by  increasing  the  activity  of  the  expulsive 
apparatus  may  be  divided  into — 

(1)  Those  which  increase  the  rapidity  of  the  ciliary  motion 
in  the  tracheal  mucous  membrane. 

(2)  Those  which  increase  the  activity  of  the  respiratory 
centre. 

We  have  no  direct  experiments  or  observations  on  the  rapidity 
of  the  ciliary  motion  in  the  bronchial  mucous  membrane  of  the 
higher  animals,  but  ammonia  has  been  found  to  increase  its 
rapidity  in  the  mucous  membrane  of  the  frog. 

The  remedies  which  increase  the  activity  of  the  respiratory 
centre  are :  strychnine,  ammonia,  emetine,  ipecacuanha,  bella- 
donna, atropine,  senega,  and  saponine.  They  are  used  more 
especially  in  cases  of  bronchitis  where  the  expectoration  is 
imperfect. 

The  chief  expectorants  have  been  divided  into  depressant  and 
stimulant.     Thoy  are  as  follows :— 


chap,  x.]      ACTION  OP  DKUGS  ON  EESPIEATION. 


255 


Depeessant  Expectorants.         Stimulating  Expectoeants. 


Generally  tending  to  depress 
the  heart,  lessen  blood-pressure, 
and  increase  secretion. 

Antimonial  preparations, 

Tartar  emetic. 
Alkalies. 
Ipecacuanha. 

Emetine, 
Lobelia. 

Lobeline. 
Jaborandi. 

Pilocarpine, 
Apomorphine. 
Quebracho. 

Quebrachine 
Potassium  iodide, 


Balsams 


Terebin- 
thinates 


Generally     stimulating      the 
heart,  increasing  blood-pressure, 
and  diminishing  secretion. 
Acids. 

(chloride, 
carbonate, 
hydrate 
(Ammonia). 
Nux  vomica. 

Strychnine. 
Senega. 

Saponine. 
Squill. 

Benzoin. 
Benzoic  acid. 
Balsam  of  Tolu. 
.Balsam  of  Peru. 
/Wood  tar. 
Terebene. 
Turpentine. 
( Oleum  Pini 

Sylvestris. 
Oleum  Pini 
VPumilionis. 
Sulphur. 

Saccharine    j  Syrups, 
substances  I  Liquorice. 

Adjuncts. — One  of  the  most  powerful  adjuncts  to  expectorants 
is  an  emetic,  which  frequently  will  clear  the  lungs  and  save  life 
in  cases  of  chronic  bronchitis  with  impending  suffocation,  when 
ordinary  expectorants  have  completely  failed. 

One  of  the  emetics  most  commonly  employed  in  such  cases  is 
ipecacuanha,  either  alone  or  combined  with  squill,  e.g.  half  a  fluid 
ounce  each  of  ipecacuanha  wine  and  oxymel  of  squills.  When 
there  is  great  depression,  however,  and  the  circulation  is  very 
feeble,  carbonate  of  ammonium  is  to  be  preferred. 

Another  powerful  adjunct  is  warmth  and  moisture  in  the 
room  in  which  the  patient  is  living,  and  this  is  best  secured  by 
means  of  steam  brought  well  into  the  room  from  a  kettle  placed 
upon  the  hob.  The  kettle  used  should  either  be  furnished  with  a 
very  long  spout,  as  in  the  case  of  the  ordinary  bronchitis  kettle, 
or  a  long  tube  made  of  a  piece  of  stout  brown  paper  tied  around 
with  a  string  may  be  used  to  convey  steam  into  the  room  from 
the  nozzle  of  an  ordinary  kettle. 


256     PHARMACOLOGY  AND  THERAPEUTICS,  [seot.i. 

Respirators  are  also  serviceable,  by  preventing  the  entrance 
of  cold  air  into  the  trachea.  Many  persons,  forgetting  that  the 
mouth  is  part  of  the  digestive  tract,  and  that  the  nose  is  the 
proper  entrance  to  the  respiratory  tract,  breathe  through  their 
mouth ;  the  consequence  is,  that  the  cold  air  passes  down  the 
trachea  without  being  previously  warmed.  In  the  nose  we  bave 
a  special  arrangement  for  warming  the  air.  The  turbinated 
bones  present  an  enormous  warming  surface,  like  some  recently- 
invented  stoves,  and  moreover,  a  special  arrangement  is  made  for 
allowing  a  free  flow  of  blood  through  this  mucous  membrane  by 
its  being  loosely  instead  of  firmly  attached  to  the  turbinated  bones. 
Its  vessels  are  therefore  capable  of  great  and  rapid  distension, 
so  as  to  allow  the  air  to  be  readily  warmed  in  cold  weather. 

Most  respirators  are  made  simply  to  go  over  the  mouth,  and 
their  advantage  is  that  they  force  people  to  breathe  through 
their  nose,  or  warm  the  air  if  they  cannot  do  so,  and  continue  to 
breathe  through  the  mouth.  In  many  persons  the  same  end  may 
be  gained  by  forcing  them  to  wear  an  invisible  respirator.  An 
instrument  is  sold  bearing  this  name,  consisting  of  a  thin  plate 
of  metal ;  but  what  is  perhaps  quite  as  good,  or  better,  is  a  sove- 
reign or  half-sovereign  placed  between  the  lips  and  teeth.  Patients 
are  thus  forced  to  keep  the  mouth  shut  in  order  to  prevent  it  from 
falling  out,  and  its  value  makes  them  careful  about  losing  it. 

It  is  often  forgotten  too  that  passages  and  disused  rooms  are 
nearly  as  cold  as  the  external  air,  and  many  delicate  people  who 
would  never  dream  of  going  outside  in  cold  weather  will,  without 
thinking,  walk  through  cold  passages  and  in  rooms  without  fires. 
Warm  clothing,  especially  over  the  shoulders,  neck,  and  chest, 
is  very  useful,  and  its  utility  is  recognised  by  the  common  employ- 
ment of  so-called  chest  protectors  made  of  chamois  leather  and 
red  flannel. 

Other  adjuncts  are  friction  to  the  chest  with  stimulating 
liniments ;  mustard  leaves,  warm  poultices  and  the  application  of 
plasters  ;  the  emplastrum  calefaciens  (B.P.)  or  emplastrum  picis 
cum  cantharide  (U.S.P.)  is  especially  useful  in  chronic  bronchitis. 

Arrest  of  Colds. — Catarrhal  affections  of  the  respiratory 
passages  may  be  excited  by  irritants  of  various  kinds,  and  it  is 
probable  that  these  irritants  are  frequently  living  organisms. 
The  form  of  coryza  usually  called  hay-fever  is  probably  due  to 
irritation  of  the  nasal  mucous  membrane  by  pollen-grains  com- 
mencing to  grow  on  it  and  sending  pollen-tubes  into  its  substance. 

Other  forms  of  respiratory  catarrh,  e.g.  measles  and  influenza, 
are  probably  associated  with  specific  microbes. 

When  the  respiratory  mucous  membrane  is  perfectly  healthy 
it  is  probable  that  the  invading  organisms  are  quickly  expelled 
or  destroyed  (p,  85)  so  that  no  injury  results.  But  when  the 
resisting  power  of  the  mucous  membrane  is  weak,  either  on 
account  of  general  constitutional  tendencies,  or  from  local  anil 


chap.x:]      ACTION  OF  DEUGS  ON  EESPIEATION.  257 

temporary  condition  of  congestion  due  to  a  chill  (p.  252),  the 
microbes  may  begin  to  grow  and  cause  great  irritation. 

Among  the  remedies  useful  in  arresting  colds  we  may  recog- 
nise antiseptics,  which  destroy  microbes,  and  also  sedatives, 
which  remove  congestion. 

_  Hay-fever  has  been  treated  by  Binz  with  a  watery  solution  of 
quinine  in  order  to  stop  the  growth  of  organisms  in  the  nose.  In 
some  cases  this  treatment  is  successful.  There  is  a  form  of  cold 
sometimes  known  as  influenza-cold.  Like,  true  influenza  it  is 
extremely  infectious  and  is  easily  communicated,  not  only  by  one 
member  of  a  family  to  another,  but  even  by  casual  visitors.  It 
sometimes  begins  as  a  cold  in  the  head,  passes  down  the  throat 
to  the  trachea  and  bronchi,  leading  to  severe  bronchitis  with 
much  depression  and  occasionally  also  to  gastro-intestinal  catarrh. 
Sometimes  it  begins  in  the  throat  and  spreads  upwards  into  the 
nostrils  and  downwirds  into  the  air-passages.  It  may  frequently 
be  arrested  or  rendered  less  severe  by  the  use  of  dilute  carbolic 
acid  applied  to  the  nostrils  in  the  form  of  spray  or  by  a  syringe 
or  rasal  douche  when  the  cold  begins  in  the  head.  When  the  cold 
begins  in  the  throat  it  may  be  arrested  by  the  use  of  a  carbolic 
acid  gargle,  and  such  a  gargle  is  also  useful  when  the  cold  begins 
in  the  head  and  is  spreading  down  the  throat. 

Inhalations  of  carbolic  acid  and  ammonia  appear  to  be  fre- 
quently useful  in  arresting  colds.  It  seems  probable  that  their 
effect  may  be  due  partly  to  an  antiseptic  action  and  partly  to  their 
lessening  congestion.  Carbolic  acid  inhalations  appear  to  be,, 
useful  in  whooping-cough,  probably  from  an  antiseptic  action. 

Camphor  inhaled  and  also  taken  internally  is  useful  in  arrest- 
ing colds,  though  it  may  be  rather  hard  to  give  an  explanation  of 
its  modus  operandi. 

The  sedatives  which  remove  congestion  of  the  nasal  mucous 
membrane  may  be  either  general  or  local.  Amongst  the  local  may 
be  mentioned  bismuth,  bismuth  and  morphine,  and  cocaine ;  and 
amongst  the  general,  preparations  of  opium,  especially  Dover's 
powder,  and  aconite. 

Selection  of  Remedies  in  the  Treatment  of  Cough. 

Cough,  as  I  have  already  said,  is  a  reflex  act  which  is  per- 
formed hy  means  of  a  reflex  mechanism,  and  is  adopted  for  the 
purpose  of  expelling  foreign  bodies  from  the  air-passages.  It  is 
evident  that,  when  the  source  of  irritation  may  be  removed  by 
efforts  at  coughing,  these  efforts  are  useful,  and  require  to  be  sus- 
tained rather  than  prevented ;  but  if  the  irritant  cannot  be  re- 
moved, the  effort  of  coughing  is  injurious  rather  than  beneficial, 
and  the  same  is  the  case  when  the  amount  of  effort  is  dispro- 
portionately great  to  the  good  that  it  effects.  In  these  cases  we 
must  try  to  lessen  the  cough. 


258  PHAKMACOLOGY  AND  THERAPEUTICS,     [sect.  I. 

The  source  of  irritation  in  the  respiratory  passages  may  either 
he  free  in  the  lumen  of  the  bronchial  tuhes,  or  may  he  situated 
in  the  mucous  membrane  lining  the  bronchi,  or  in  the  substance 
of  the  lung  itself.  Thus  we  may  have  foreign  substances,  such 
as  dust,  which  have  been  inhaled,  or  mucus  secreted  from  the 
bronchi,  resting  on  the  surface  of  the  mucous  membrane,  and 
leading  to  irritation.  Such  foreign  matter  may  be  expelled  by 
coughing,  and  so  may  purulent  matter  lying  in  a  cavity,  and  the 
cough  may  be  useful  by  expelling  them. 

But  if  the  irritation  be  simply  due  to  a  congested  condition  of 
the  bronchial  mucous  membrane  ;  to  congestion  or  consolidation 
of  the  lung-tissue  itself;  to  a  caseous  or  calcareous  nodule  which 
is  firmly  embedded  in  the  lung ;  or  to  inflammation  of  the  pleura, 
it  is  evident  that  the  efforts  at  coughing  will  not  remove  the 
irritant,  but  will  rather  tend  to  produce  exhaustion;  and  con- 
sequently we  must  either  try  to  remove  the  source  of  irritation 
by  other  means,  or  to  lessen  the  irritability  of  the  nervous  me- 
chanism by  which  coughing  is  produced.  Where  the  cough  is 
due  to  irritation  caused  by  indigestion  we  may  give  alkalies  to  re- 
lieve acidity,  but  we  sometimes  find  that  a  blue  pill  and  a  black 
draught  are  amongst  the  most  efficient  remedies  for  coughs  of 
this  character,  by  the  permanently  beneficial  action  they  exert  on 
the  digestion.  When  there  is  irritation  of  the  pharynx,  as  well 
as  of  the  trachea,  mucilaginous  substances,  such  as  jujubes  or 
linseed  tea,  are  exceedingly  useful. 

Where  cough  depends  on  congestion  of  the  mucous  mem- 
brane of  the  trachea  or  bronchi,  we  not  unfrequently  find  that  the 
inhalation  of  cold  air,  by  causing  contraction  of  the  vessels,  and 
lessening  the  congestion,  will  arrest  the  cough,  so  that  patients 
are  able  to  walk  out  on  a  cold  frosty  morning  for  a  length  of  time 
without  coughing.  On  coming  into  a  warm  room  the  vessels  of 
the  respiratory  mucous  membrane  again  dilate :  the  mucous 
membrane  becomes  congested,  and  the  congestion  leads  to  violent 
and  prolonged  efforts  at  coughing.  In  such  cases  counter-irrita- 
tion over  the  neck,  upper  part  of  the  chest,  and  between  the 
shoulders  is  useful,  probably  by  causing  contraction  of  the  vessels 
(p.  252),  and  thus  lessening  congestion.  But  congestion,  not 
only  of  the  trachea  and  bronchi,  but  also  of  the  smaller  bronchial 
tubes,  may  be  relieved,  not  only  by  counter-irritation,  but  by  in- 
ducing secretion.  Congestion  of  the  smaller  bronchi  indicated 
by  loud  whistling  rales  all  over  the  chest,  is  often  accompanied 
by  great  shortness  of  breath.  The  inhalation  of  hot  aqueous 
vapour  tends  to  relieve  the  congestion  by  inducing  secretion,  but 
more  powerful  agents  still  are  antimony,  ipecacuanha,  and  apo- 
morphine.  In  such  a  condition  as  the  one  just  mentioned,  where 
secretion  is  absent  and  congestion  is  great,  one  or  other  of  these 
drugs  should  be  given  frequently  until  secretion  occurs  freely,  as 
indicated  by  abundant  moist  rales  in  the  chest. 


chap,  x.]      ACTION  OF  DEUGS  ON  EESPIEATION.  259 

Along  with  these  depressant  expectorants,  some  preparation 
of  opium  should  be  given,  in  order  to  lessen  the  cough,  which  at 
this  stage  is  of  no  advantage.  It  is  advisable  not  to  stop  the 
administration  of  these  expectorants  immediately  on  the  occur- 
rence of  secretion,  but  to  continue  them  for  some  time  longer, 
and  gradually  to  lessen  their  amount.  "When  secretion  has  be- 
come copious,  either  from  the  administration  of  depressant  ex- 
pectorants or  from  the  natural  course  of  the  disease,  we  have 
resort  to  such  drugs  as  will  tend  to  cause  its  expulsion,  and  also 
to  lessen  its  formation.  Amongst  those  which  tend  to  lessen  its 
formation  are  balsams  and  terebinthinates  (p.  255),  and  those 
which  tend  to  assist  expulsion  have  already  been  mentioned  (p. 
254).  Along  with  these  we  generally  combine  some  preparation 
of  opium  if  the  cough  is  disproportionately  severe,  and  in  chronic 
bronchitis  cod-liver  oil  (p.  254)  is  perhaps  the  most  efficient  of 
all  remedies. 

Action  of  Drugs  on  the  Bronchi. —  The  bronchi  contain 
muscular  fibres  in  their  walls,  which  appear  to  maintain  a  state 
of  tonic  contraction  similar  to  that  of  the  arteries.  The  motor 
fibres  which  supply  these  muscles  are  contained  in  the  vagi. 
When  one  vagus  is  cut  the  bronchi  of  the  corresponding  lung  ex- 
pand, and  when  the  peripheral  end  of  the  cut  vagus  is  stimulated, 
the  bronchi  contract  so  much  as  sometimes  almost  to  close  com- 
pletely ;  but  the  vagi  appear  to  contain  bronchial-dilating  fibres, 
as  well  as  bronchial-constricting,  so  that  irritation  of  the  peripheral 
end  of  a  cut  vagus  may  sometimes  cause  marked  dilatation  instead 
of  contraction,  and  sometimes  primary  contraction  followed  by 
dilatation.  The  vagi  also  contain  afferent  fibres,  passing  from 
the  bronchi  to  the  nerve-centres,  and  these  afferent  fibres  have 
also  a  twofold  action,  so  that  when  the  central  end  of  one  cut 
vagus  is  irritated,  the  irritation  may  cause  either  reflex  contrac- 
tion or  reflex  dilatation  of  the  bronchi  in  the  other  lung.  It  is 
probable  that  there  are  two  cerebro- spinal  centres  :  one  produc- 
ing dilatation  and  the  other  contraction.  Atropine  completely 
paralyses  either  the  constricting  fibres  of  the  vagus  or  their  ter- 
minations in  the  bronchi,  so -that  after  a  very  small  dose  stimu- 
lation of  the  peripheral  end  of  the  cut  vagus  no  longer  causes 
contraction.  Ether  probably  paralyses  the  cerebro-spinal  centre 
for  contraction,  so  that  irritation  of  the  central  ends  of  a  divided 
vagus  causes  expansion  instead  of  contraction  in  the  bronchi  of 
the  other  lung.  Small  doses  of  nicotine  have  a  powerful  effect 
in  expanding  the  bronchi,  but  the  mode  of  action  of  the  drug  has 
not  been  determined.1 

Pathology  of  Bronchial  Asthma.— The  attacks  of  dyspnoea 
which  occur  in  spasmodic  asthma  in  all  probability  depend  upon 
spasmodic  contraction  of  the  unstriped  muscular  fibres  in  the 


'  Eov  and  Graham  Brown,  Journ  of  Phys.  vol.  vi, 

s2 


266  PHAEMACOLOGY  AND  THBEAPEUTICS.      [sect.  r. 

bronchi.  In  some  cases  no  definite  cause  can  be  assigned  for 
the  occurrence  of  these  attacks,  though  a  gouty  tendency  in  the 
patient,  or  the  imperfect  elimination  of  waste  products,  as  in 
renal  diseases,  increases  the  tendency  to  their  occurrence.  In 
other  eases  they  appear  to  be  occasioned  by  irritation,  either  in 
the  mucous  membrane  of  the  respiratory  tract  or  irritation  of 
some  other  part  of  the  body.  Thus  they  appear  sometimes  to 
be  brought  on  reflexly,  by  irritation  of  the  nose  by  polypi,  by 
certain  odours,  or  the  inhalation  of  irritating  dust,  especially 
pollen  of  ,grass,  or  by  congestion  of  the  mucous  membrane  in 
ordinary  coryza.  Sometimes  irritation  of  the  pharynx  by  en- 
larged tonsils  appears  to  bring  them  on,  and  they  frequently 
arise  from  bronchial  catarrh.  At  other  times  they  may  occur  in 
consequence  of  indigestion,  constipation,  of  worms  in  the  intes- 
tine, of  disease  of  the  uterus  or  ovaries,  or  of  pregnancy. 

Treatment  of  Asthma. — In  cases  where  the  cause  of  the 
attacks  can  be  ascertained,  the  cause  is  to  be  removed.  Thus  in 
gouty  patients  the  free  use  of  water  as  a  beverage,  and  the  ad- 
ministration of  iodide  and  bromide  of  potassium  or  of  salicylate 
Of  sodium  may  be  useful.  In  renal  asthma  the  diet- must  be  chiefly 
•farinaceous  and  fatty,  meat  and  beef-tea  being  sparingly  given, 
>so  as  to  avoid  the  accumulation  of  waste  products  in  the  system, 
•and  caffeine  (pp.  433,  434)  may  be  given  to  aid  their  elimination. 
The  asthma  of  dyspepsia,  and  also  that  of  constipation,  may 
possibly  be  due  partly  to  the  presence  of  abnormal  digestive  pro- 
ducts in  the  blood,  as  well  as  to  irritation  of  the  mucous  mem- 
brane of  the  stomach  or  intestine.  In  dyspeptic  asthma  pepsin 
has  proved  very  useful;  emetics  are  sometimes  of  service,  pro- 
Jbably  by  removing  irritating  substances  (p.  255),  and  ipecacu- 
anha may  possibly  have  some  special  action  of  its  own  on  the 
mucous  membrane,  in  addition  to  its  emetic  action.  Constipation 
is  to  be  treated  by  laxatives  (p.  388)  and  cholagogues  (p.  404),  and 
worms  by  vermifuges  (p.  408).  Polypi  in  the  nose  and  enlarged 
tonsik  are  to  be  removed,  and  for  congestion  of  the  mucous  mem- 
brane of  the  nose  or  throat,  carbolic  acid  lotion  may  be  used 
(p.  257). 

The  medicine  most  usually  employed  to  prevent  recurrence 
of  the  attack  is  lobelia  inflata.  The  exact  mode  of  action  of  this 
drug  is  not  known,  but  the  general  symptoms  produced  by  it  so 
closely  resemble  those  of  tobacco  that  it  is  often  known  as  Indian 
tobacco,  and  possibly  its  action  on  the  bronchial  tubes  may  be 
somewhat  the  same  as  those  of  nicotine.  During  the  attacks  of 
■spasmodic  asthma  more  relief  is  usually  afforded  by  the  inhala- 
tion of  smoke  of  various  kinds  than  by  any  other  means.  The 
smoke  of  tobacco,  of  the  leaves  of  various  species  of  datura:,  of 
paper  impregnated  with  potassium  nitrate,  or  with  a  mixture  of 
potassium  nitrate  and  chlorate ;  of  pastiles  and  of  various  powders, 
which  probably  are  principally  composed  of  powdered  datura- 


chap,  x.]      ACTION  OF  DEUGS  ON  EESPIEATION.  261 

leaves,  mixed  with  powdered  nitre,  and  perhaps,  also,  with  ipe- 
cacuanha, all  prove  useful.  The  action  of  all  these  smokes  is 
probably  the  same  as  that  of  nicotine,  for  Vohl  and  Eulenberg1 
have  shown  that  the  active  principles  in  tobacco-smoke  really 
are  not  nicotine  alone,  but  are  the  products  of  the  dry  distilla- 
tion of  tobacco-leaves,  consisting  chiefly  of  pyridine,  collidine* 
and  allied  substances,  which  resemble  nicotine  in  action,  and  are 
present  along  with  it  in  the  smoke.  The  same  products,  but  in 
different  proportions,  are  obtained  by  the  dry  distillation  of  other 
organic  bodies.  The  proportion  in  which  the  different  bases  are 
present  depends  both  on  the  nature  of  the  substances  subjected 
to  dry  distillation,  and  on  the  amount  of  oxygen  present  during 
the  process.  When  much  oxygen  is  present,  bodies  of  higher 
atomic  weight  and  less  volatile  than  those  lower  in  the  series 
are  formed,  much  collidine  being  produced  when  tobacco  is 
smoked  as  a  cigar,  while  pyridine  is  the  chief  product  when  it  is 
smoked  in  a  pipe.  It  is  probable  that  the  admixture  of  nitre 
with  paper  or  with  powdered  leaves  acts  beneficially  by  producing 
a  different  mixture  of  organic  bases  than  would  be  produced  by 
burning  the  paper  or  the  leaves  alone,  and  that  we  must  look  to 
bodies  allied  to  collidine  for  the  relief  of  asthma. 

'Arch.  Pharm.  (2),  1873,  vol.  cxlvii.  130-166. 


2G2  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 


CHAPTEE  XI. 
ACTION  OF  DEUGS  ON  THE   CIECULATION. 

It  has  already  been  mentioned  that  the  cells  of  which  higher 
organisms  are  composed  live  in  the  intercellular  fluid  or  lymph 
which  bathes  them. 

This  nutritive  fluid  is  continually  being  renewed  by  fresh 
supplies  exuding  from  the  blood-vessels  into  the  lymph-spaces 
which  surround  the  cells,  the  excess  being  removed  by  absorption 
either  by  the  veins  or  by  the  lymphatics.  Besides  this,  an  inter- 
change of  gases  (internal  respiration)  and  of  solids  takes  place 
by  diffusion  between  the  lymph  and  the  blood. 

Wben  the  circulation  stops,  internal  respiration  is  arrested, 
and  the  cells  die.  But  they  do  not  all  die  at  the  same  time,  for 
some  are  able  to  live  longer  without  fresh  supplies  of  oxygen 
than  others.  The  order  in  which  they  die  is  (1)  the  cells  of  the 
initiative  nerve-centres,  as  the  brain  ;  (2)  those  of  the  automatic 
and  reflex  centres ;  (3 )  nerve-fibres  (which  are  modified  nerve- 
cells)  ;  (4)  unstriated  muscles  {  (5)  striated  muscles. 

Arteries  and  Veins. — It  is  important  in  this  respect  to  re- 
member tbat  it  is  only  so  long  as  blood  is  in  the  arteries  that  it 
is  available  for  the  nutrition  of  cells.  Once  in  the  veins  it  is 
useless  for  nutrition ;  and  were  it  not  that  it  readily  passes  from 
the  veins  into  the  arteries  again,  it  might  as  well  be  outside  the 
body  for  any  purposes  of  nutrition. 

The  veins  are  very  capacious,  and  when  dilated  to  their 
utmost,  they  can  alone  hold  all  the  blood  the  body  contains, 
and  more.  During  life  they  are  constantly  kept  more  or  less  in 
a  state  of  contraction  by  the  action  of  the  nervous  system,  but 
when  they  become  completely  dilated,  as  after  death,  all  the 
blood  flows  into  them,  leaving  the  arteries  empty.  It  is  there- 
fore possible,  as  Ludwig  has  well  expressed  it,  to  bleed  an  animal 
into  its  own  veins.  Schiff  has  shown  that  when  the  blood-vessels 
relax  as  they  do  after  section  of  the  medulla  oblongata,  the  whole 
of  the  blood  of  another  animal  as  large  as  the  one  experimented 
upon  must  be  introduced  in  addition  to  its  own,  in  order  to  raise 
the  pressure  within  the  vessels  to  the  normal.  Even  this  is  in- 
sufficient to  keep  up  the  pressure,  for  the  vessels  go  on  still 
dilating,  and  the  pressure  falls,  notwithstanding  the  large  quan* 


chap,  xi.]    ACTION  OF  DEUGS  ON  THE  CIRCULATION.     263 

tity  of  blood  which  is  present  in  them.  It  is  therefore  evident 
that  the  normal  action  of  the  vasomotor  centres  is  more  than 
equivalent,  for  .the  purposes  of  circulation,  to  as  much  blood 
again  as  the  animal  possesses.  "Weakened  power  of  these  centres 
is  to  a  certain  extent  equivalent  to  bleeding,  and  increased  power 
has  a  similar  effect  to  an  increase  in  the  quantity  of  blood  in  the 


Blood-pressure.— The  continuity  of  the  circulation  of  blood 
through  the  capillaries  is  not  maintained  by  the  heart  alone : 
the  elastic  pressure  of  the  arteries  on  the  blood  within  them  plays 
ajnost  important  part,  and  indeed  during  the  cardiac  diastole  the 
circulation  is  maintained  entirely  by  this  elastic  pressure. 

If  the  arterioles  or  capillaries  through  which  the  arterial 
system  empties  itself  into  the  veins  are  much  contracted,  so  that 
the  blood  can  flow  only  slowly  through  them,  the  heart  may  stop, 
and  yet  the  blood-pressure  may  remain  for  many  seconds  almost 
Unchanged.  But  if  the  arterioles  or  capillaries  are  dilated,  the 
arteries  quickly  empty  themselves  into  the  veins,  arterial  pres- 
sure rapidly  falls,  and  circulation  soon  stops. 


tm.  83.— Diagram  to  illustrate  the  effects  of  the  horizontal  and  vertical  position  on  the  circulation 
of  the  frog  in  shock,  a,  normal  ciiculation  in  the  upright  position.  6,  circu'ation  after  dilata- 
tion of  the  veins  has  been  produced  by  a  blow  on  the  intestines.  The  blood  does  not  reach  the 
heart,  and  it  beats  empty,  so  that  the  circulation  stops,  c  shows  the  circulation  ina  horizontal 
position  after  the  veins  have  been  dilated,  as  in  b.  The  veins  are  still  dilated,  but  the  .blood 
reaches  the  heart,  and  the  circulation  is  carried  on.  Fig.  c  is  perhaps  too  diagrammatic,'  as  it 
appears  to  show  an  empty  space  or  air  in  the  veins.  In  reality  the  veins,  being  very  thic- 
walled,  collapse.  Fig.  6  is  open  to  the  same  objection,  but  if  we  suppose  ourse  ves  to  be  look- 
ing at  the  vein  from  the  front  instead  of  in  section,  6  represents  almost  exactly  what  I  have 
myself  seen  in  repeating  Goltz's  experiment. 

I  use  the  words  arterioles  and  capillaries  as  synonymous, 
because  it  is  almost  certain  that  the  capillaries  do  contract.  In 
most  cases  where  contraction  has  occurred  in  the  peripheral 
vessels,  it  is  difficult  or  impossible  to  say  whether  its  seat  is  in 
the  capillaries  or  arterioles. 

The  action  of  the  heart  is  to  pump  the  blood  out  of  the  veins 
into  the  arteries,  and  this  it  can  only  do  when  the  blood  reaches 
it.  If  the  veins  are  much  dilated  and  the  animal  is  in  an  up- 
right position,  no  blood  may  reach  the  heart,  or  so  little  blood 
that  its  pulsations  are  practically  useless.  This  is  seen  in  the 
frog  when  dilatation  of  the  large  veins  has  been  renexly  pro- 
duced by  striking  the  intestines  (Fig.  836).  When  the  animal  is 
laid  flat,  the  blood  flows  into  the  heart,  and  then  it  works  nor- 
mally. It  is  probable  that  a  similar  condition  occurs  in  man,  as 
one  of  the  factors  in  shock ;  and  in  this  condition,  as  well  as  in 
fainting,  or  failure  of  the  heart's  action  from  the  effect  of  drugs, 


264 


PHARMACOLOGY  AND  THEEAPEUTICS.      [sect,  i. 


as  chloroform,  or  other  causes,  the  person  should  be  laid  flat, 
with  the  limbs  raised  so  that  the  blood  may  flow  out  of  them 
into  the  heart,  and  with  the  head  low  (either  perfectly  level  with 
the  body  or  depressed  below  it),  in  order  to  permit  of  an  in-, 
creased  supply  of  blood  to  the  intra-cranial  nerve-centres. 

Fainting  and  Shock. — In  fainting  there  is  sudden  uncon- 
sciousness, which  appears  to  be  caused  by  sudden  arrest  of  the 
supply  of  blood  to  the  brain.  This  arrest  may  be  due  to  a  rapid 
fall  in  blood-pressure,  either  from  stoppage  of  the  heart,  rapid 
dilatation  of  the  arterioles,  or  sudden  removal  of  pressure  from 
the  larger  vessels.  It  is  possible  that  these  conditions  may  be  as- 
sociated with  spasmodic  contraction  not  only  of  the  vessels  of  the 
face  and  surface  generally,  but  of  those  supplying  the  brain  itself. 
Tbe  effect  of  sudden  change  from  a  horizontal  to  an  upright  pos- 
ture in  producing  syncope  has  already  been  mentioned  (p.  205). 
Sudden  removal  of  external  pressure  from  the  great  vessels  acts 
upon  both  arteries  and  veins.  It  removes  external  support  from 
the  arteries,  and  allows  them  to  yield  more  readily  to  the  in- 
fluence of  the  blood-pressure,  and  by  their  dilatation  to  lessen  it. 
It  allows  the  large  veins  also  to  dilate,  and  blood  to  stagnate  in 
them.  Its  influence  is  readily  seen  when  fluid  is  removed  too 
suddenly  from  the  abdomen,  and  external  pressure  by  a  bandage 
hot  supplied  in  its  place,  as  in  cases  of  ascites. 

It  is  seen,  perhaps,  even  more  strikingly,  where  the  bladder 
*has  been  allowed  to  become  distended  and  is  suddenly  emptied. 
The  effect  of  this  is  shown  in  Fig.  84.   In  a  the  bladder  is  repra- 


Carotid  artery  (full) 


Aorta  tense 

Veins  tense  and  mode- 1 
ratelyfullf 


Bladder  (full) 


e-~ 


"  Carotid  artery  (empty). 


Aorta  las. 

Veins  lax  and  full. 


Bladder  (empty). 


]?ig.  84.— Diagram  to  show  the  effects  on  the  cerebral  circulation 'of  rapidly  emptying  the  bladder. 

sented  as  full,  and,  the  pressure  within  the  abdomen  being  con- 
siderable, the  veins  are  prevented  from  dilating,  the  heart  is  well 
supplied  with  blood,  and  the  circulation  in  the  brain  is  active. 
In  b,  the  bladder  is  represented  as  empty,  and  the  abdominal 
contents  being  diminished,  so  that  the  intra-abdominal  pressure 
is  lessened,  not  only  do  the  aorta  and  other  vessels  become  lax 
from  loss  of  the  external  pressure,  but  the  veins  dilate,  the  hear$ 


chap,  xi.]    ACTION  OF  DEUGSON  THE  CIECULATION.     265 

is  imperfectly  supplied  with  blood,  the  cerebral  circulation  fails, 
and  syncope  ensues.  This  occurs  more  readily  just  after  waking, 
before  the  vaso-motor  centre  has  recovered  its  usual  tone,  so  that 
one  of  the  most  favourable  conditions  for  its  occurrence  is  when 
a  man  jumps  suddenly  into  the  upright  position  and  empties  his 
bladder  immediately  on  waking.  The  consequence  of  this  some- 
times is  that  he  falls  down  suddenly,  quite  insensible,  during  the 
act  of  micturition.  I  have  seen  one  case  in  which  the  tendency 
appeared  to  be  increased  by  the  practice  of  opium-eating,  pro- 
bably from  the  diminished  excitability  of  the  vaso-motor  centre 
produced  by  the  drug.  It  is  evident  that  the  danger  will  be  in- 
creased if  the  intervals  between  the  systoles  of  the  heart  are  pro- 
longed, and  it  is  the  combination  of  the  natural  tendency  to 
syncope,  produced  by  large  doses  of  digitalis,  with  that  caused  by 
the  sudden  assumption  of  the  upright  posture,  and  by  the  rapid 
emptying  of  the  bladder,  which  renders  micturition  in  the  upright 
posture  so  excessively  dangerous  in  persons  under  the  action  of 
digitalis,  and  leads  so  frequently  to  death. 

It  is  evident  that  fainting  may  be  prevented  by  increasing  the 
blood-pressure  in  the  brain  locally,  or  throughout  the  body  gene- 
rally. To  increase  it  locally  the  head  of  a  fainting  person  should 
be  allowed  to  lie  level  with  the  body,  or  a  little  below  it,  and  on 
no  account  raised  even  by  pillows.  A  fainting  fit  may  indeed 
often  be  prevented  by  sitting  with  the  head  hanging  between  the 
knees.  It  may  also  be  prevented  or  removed  by  such  conditions 
as  raise  the  general  blood-pressure,  e.g.  a  draught  of  cold  water, 
which  causes  contraction  of  the  gastric  vessels,  or  a  sniff  of  am- 
monia or  acetic  acid,  which  stimulates  the  nasal  nerves,  and 
causes  reflex  contraction  of  the  vessels  generally.  In  some  parts 
of  India  the  natives  are  accustomed  to  bring  persons  round  from 
a  faint  by  compressing  the  nostrils  and  holding  the  hand  over 
the  mouth,  so  as  completely  to  stop  respiration.  The  accumula- 
tion of  carbonic  acid  in  the  blood  irritates  the  vaso-motor  centre, 
raises  the  blood-pressure,  and  thus  probably  tends  to  bring  the 
person  round. 

In  shock  there  is  no  unconsciousness,  but  the  failure  of  the 
circulation  is  even  more  profound  than  in  syncope.  Its  pathology 
is  not  perhaps  exactly  ascertained,  but  it  probably  depends  to  a 
great  extent  on  a  paralytic  distension  of  the  great  veins,  as  in 
Goltz's  experiments.  I  have  found  that  in  shock  produced  in  a 
similar  manner  in  a  rabbit  the  blood-pressure  could  be  raised 
from  two  inches  up  to  two  and  a  half  by  the  inhalation  of  am- 
monia. 

Schema  of  the  circulation. — In  order  to  understand  the  action  of  drugs 
on  the  circulation  it  is  absolutely  necessary  to  have  a  clear  idea  regarding  the 
effect  of  the  heart  and  capillaries  in  maintaining  the  blood-pressure.  This 
is  best  obtained  by  using  a  schema  which  can  be  easily  made  from  a  spray- 
apparatus  (Pig.  85).    By  removing  the  glass  or  metal  tube  from  one  of  these, 


266 


PHAKMACOLOGY  AND  THEEAPEUTICS.      [sect.  t. 


and  attaching  a  nozzle  with  a  small  stopcock  to  the  india-rubber  tube  in  its 
stead,  we  obtain  a  very  good  schema  of  the  circulation ;  and,  by  imitating  on 
it  the  changes  which  occur  in  the  heart  and  vessels,  we  may  form  a  much 
clearer  idea  of  them  than  we  could  otherwise  do.  The  india-rubber  ball 
will  represent  the  heart ;  the  elastic  bag,  surrounded  by  netting,  will  repre- 
sent the  elastic  aorta  and  larger  arteries;  and  the  stopcock,  which  regulates 
the  size  of  the  aperture  through  which  the  air  escapes,  will  represent  the 
small  arteries  and  capillaries,  whose  contraction  or  dilatation  regulates  the 
flow  of  blood  from  the  arteries  into  the  veins.  We  may  judge  of  the  tension 
in  the  arteries  by  the  distension  of  the  bag,  or  still  better,  we  may  connect 
the  tube  between  it  and  the  stopcock  with  a  mercurial  manometer,  and 
estimate  the  tension  by  the  height  of  the  mercurial  column  which  it  sustains. 
If  we  turn  the  stopcock  so  as  to  present  some  resistance  to  the  escape  of  air, 
and  then  compress  the  india-rubber  ball,  very  little  air  will  issue  from  the 


Fig.  85.— Simple  schema  of  the  circulation,  consisting  oi  a  spray-prodncer,  Dladder,  and  mercurial 
manometer.  The  elastio  ball  represents  the  heart ;  the  elastic  bag,  covered  with  netting  to 
prevent  too  great  distension,  represents  the  aorta  and  arterial  system,  and  the  bladder  represents 
the  venous  system. 

stopcock  even  while  we  are  squeezing  the  ball ;  the  greater  part  of  it  goes  to 
distend  the  bag ;  and,  when  we  cease  to  compress  the  ball,  very  little  air 
passes  through  the  stopcock.  At  the  next  squeeze,  the  bag  becomes  a  little 
more  distended ;  and  a  little  more  air  passes  through  the  stopcock,  not  only 
while  we  are  compressing  the  ball,  but  even  when  we  relax  our  grasp.  At 
each  squeeze  of  the  ball,  the  elastic  bag  becomes  tighter,  till  it  is  so  tense, 
and  contracts  so  strongly  on  the  air  inside,  that  it  can  press  all  the  extra 
amount  of  air,  forced  into  it  when  the  ball  was  compressed,  through  the 
stopcock  during  the  time  when  the  ball  is  relaxed.  When  this  is  the  case, 
every  time  we  squeeze  the  ball  we  see  the  bag  become  a  little  fuller,  and  air 
issue  more  quickly  from  the  nozzle.  At  each  relaxation,  while  the  ball  is 
refilling,  the  bag  gets  a  little  slacker,  and  the  air  passes  out  of  the  nozzle  a 
little  more  slowly,  but  never  stops  entirely.  During  the  time  the  ball  is 
filling,  the  valves  between  it  and  the  bag  and  nozzle  are  closed,  and  cut  it 
off  from  any  connection  with  them.  All  this  time,  then,  the  stream  of  air 
from  the  nozzle  must  be  entirely  independent  of  the  ball ;  it  is  produced  by 
the  contraction  of  the  elastic  bag,  and  by  it  alone.  The  bag  may  be  stretched, 
and  the  tension  of  its  walls  increased  in  consequence,  in  two  ways :  first,  by 
working  the  ball  more  quickly  or  compressing  it  more  completely ;  second, 
by  lessening  the  opening  of  the  nozzle,  and  thus  hindering  the  passage  of  air 
through  it.  One  trial  will,  I  think,  be  enough  to  show  how  much  easier  it  is 
to  alter  the  pressure  by  changing  the  size  of  the  nozzle  than  by  any  altera- 
tion in  the  working  of  the  ball,  and  to  prove  that  alterations  in  blood-pressure 


chap.  xi/J    ACTION  OP  DEUGS  ON  THE  CIRCULATION.     267 

probably  depend  much  more  on  alterations  in  the  lumen  of  the  small 
arteries  than  on  changes  in  the  action  of  the  heart. 

But  our  schema,  as  it  at  present  exists,  is  not  a  perfect  representation  of 
the  heart  and  vessels ;  for  it  draws  its  air  from  an  inexhaustible  reservoir, 
the  atmosphere,  and  is  not  obliged  each  time  to  use  that  amount  alone  which 
it  had  previously  driven  through  the  nozzle  ;  while  the  heart  can  only  use 
the  blood  which  has  been  forced  by  it  through  the  capillaries  and  returned 
to  it  by  the  veins.  In  order  to  make  our  schema  complete,  we  must  connect 
its  two  ends  by  tying  them  into  a  bladder  or  large  thin  caoutchouc  bag  (such 
as  is  used,  after  inflation,  as  a  toy  for  children),  so  that  the  air  shall  pass 
into  it  from  the  nozzle  and  be  sucked  out  of  it  by  the  elastic  ball.  This  will 
represent  the  veins.  If  we  then  repeat  the  experiment  just  described,  we 
shall  find  that,  when  we  begin  to  work  the  ball  and  stretch  the  elastic  bag 
representing  the  arteries,  the  bladder  representing  the  veins  becomes  empty 
and  collapsed ;  and  just  in  proportion  as  we  fill  the  bag  do  we  empty  the 
bladder.  If  we  now  stop,  the  air  will  gradually  escape  from  the  bag  to  the 
bladder,  till  the  air  in  both  is  of  equal  tension,  as  at  first. 

Circulation  in  the  Living  Body. — The  phenomena  of  the 
circulation  in  the  heart  and  vessels  are  very  much  the  same  as 
in  the  schema.  "When  the  heart  stands  still  (as  when  the  vagus 
is  strongly  galvanised),  the  blood  flows  from  the  arteries  into- 
the  veins  until  the  arteries  are  nearly  empty  and  the  pressure 
■within  them  falls  to  zero.  If  the  heart  now  begin  to  beat,  it 
forces  blood  into  the  elastic  aorta  and  arteries  at  each  systole, 
and  distends  them,  just  like  the  elastic  bag  of  the  schema  ; 
while  at  the  same  time  it  takes  blood  from  the  veins,  and  they 
become  empty  in  proportion  as  the  arteries  become  full.  During 
every  diastole  of  the  heart,  the  distended  aorta  and  other  arteries, 
in  virtue  of  their  elasticity,  contract  on  the  blood  they  contain, 
and  keep  it  flowing  on  through  the  capillaries  till  another  systole 
occurs ;  the  heart,  meanwhile,  being  completely  shut  off  from 
the  aorta  by  the  sigmoid  valves  (just  as  the  ball  of  the  schema 
was  shut  off  ifrom  the  elastic  bag).  In  general,  the  diastole  is 
longer  than  the  systole ;  so  that  for  the  greater  part  the  circula- 
tion through  the  capillaries  is  carried  on  by  the  elasticity  of  the 
arteries,  and  not  directly  by  the  heart.  The  arteries,  which  we 
have  supposed  to  be  at  first  empty,  gradually  become  distended 
by  the  heart,  just  as  the  elastic  bag  was  by  the  ball,  and  exert 
more  and  more  pressure  on  the  blood  in  them  (so  that  it  would 
spout  higher  ana  higher  if  one  of  them  were  cut),  till  they  are 
able  during  the  diastole  to  press  the  same  amount  of  blood 
through  the  capillaries  into  the  veins  as  had  been  pumped  into 
them  during  the  systole.  The  more  tensely  they  are  stretched, 
the  greater  is  the  pressure  they  exert  on  the  blood  they  contain  ; 
and  the  amount  of  this  is  termed  the  arterial  tension  or  blood- 
pressure.  These  two  terms  mean  the  same  thing,  and  we  use 
one  or  other  just  as  the  fancy  strikes  us.  At  each  systole,  the  fresh 
Supply  of  blood  pumped  in  by  the  heart  stretches  them  more ; 
that  is,  the  arterial  tension  rises.  Luring  each  diastole,  the 
blood  escapes  into  the  wide  and  dilatable  veins,  and  the  arteries 


268  PHAEMACOLOGY  AND  THEEAPEUTIGS.    ■  [sect.  i. 

become  less  stretched ;  that  is,  the  arterial  tension  falls.  This 
alternation  of  rise  and  fall  constitutes  the  pulse. 

Besides  the  oscillations  which  take  place  in  the  Hood- 
pressure  at  each  beat  of  the  heart,  a  rise  and  fall  in  the  form 
of  a  long  wave  occurs  at.  each  respiration..  The  wave  begins  to 
rise  just  after  inspiration  has  begun,  reaches  its  maximum  just 
after  the  beginning  of  expiration,  and  then  begins  to  fall  again 
till  a  new  wave  succeeds  it.  The  heart-beats  are  generally  quicker 
during  inspiration,  and  slower  during  expiration. 

The  blood -pressure  thus  oscillates  up  and  down  at  each 
heart-beat  and  rises  and  falls  with  each  respiration,  and  the 
average  between  the  highest  and  lowest  points  is  called  the  mean 
arterial  tension  or  mean  blood-pressure. 

Besides  the  oscillations  in  blood-pressure  due  to  the  pulse 
and  to  the  respiration,  there  are  slowly  rising  and  falling  waves 
to  which  the  name  of  Traube's  curves  is  given.  These  are  due 
to  alternate  contraction  and  relaxation  of  the  arterioles  and 
capillaries.  Bhythmical  contraction  of  the  arterioles  has  been 
observed  in  almost  all  parts  of  the  body  of  rabbits,  and  probably 
occurs  both  in  the  lower  animals  and  in  man. 

The  blood-pressure  is  not  equal  throughout  the  whole  arte- 
rial system.  It  is  greater  in  the  large  and  less  in  the  smaller 
arteries,  in  which  it  becomes  diminished  by  the  friction  between 
the  blood  and  the  arterial  walls.  It  is  also  modified  by  gravity, 
so  that  the  position  of  a  limb  may  alter  the  pressure  in  its 
arteries. 


Method  of  ascertaining  the  Blood-Pressure. 

The  blood-pressure  is  usually  estimated  in  animals  by  connecting  a  large 
artery,  such  as  the  carotid  or  femoral,  with  a  bent  tube  containing  mercury 
by  means  of  a  connecting  tube,  which  is  filled  with  a  solution  of  carbonate  of 
sodium  to  prevent  coagulation.  The  pressure  is  estimated  by  the  height  at 
which  the  mercury  stands  in  the  outer  limb  of  the  tube.  The  height  may 
either  be  read  off  with  the  eye,  or,  what  is  much  better,  it  may  be  registered 
on  a  revolving  cylinder  by  means  of  a  long  float  which  rests  upon  the  surface 
of  the  mercury,  and  bears  on  its  upper  end  a  brush  or  pen.  This  method, 
which  is  important  both  in  itself  and  as  being  the  introduction  of  the  graphio 
method  into  physiology,  we  owe  to  C.  Ludwig.  The  apparatus  is  known  as 
the  kymograph. 

Tracings  may  be  taken  upon  paper  with  a  varying  speed :  it  is  usual  to 
take  them  upon  paper  travelling  rapidly,  so  that  quick  and  small  oscillations 
due  to  the  cardiac  beats  may  not  be  lost  or  obscured  by  fusion.  The  great 
disadvantage  of  this  is  that  it  is  impossible  to  use  the  curves  directly :  they 
must  be  reduced,  and  this  is  a  work  requiring  much  time  and  labour.  When 
taken  on  a  slowly  revolving  cylinder  we  get  the  general  results  of  the  action 
of  a  drug  on  the  blood-pressure  shown  us  at  a  glance ;  and  its  effects  on  the 
form  and  rapidity  of  the  pulse  may  by  a  little  arrangement  be  recorded  from 
time  to  time  on  another  cylinder  revolving  more  rapidly. 

This  method  gives  us  both  the  blood-pressure  and  the  oscillations  which 
it  undergoes  on  account  of  the  cardiac  pulsations  and  respiration.  If  we 
wish  to  get  the  mean  blood-pressure  unaffected  by  these  oscillations,  it  is 


chap,  xi.]    ACTION  OF  DRUGS  ON  THE  CIRCULATION.     269 

done  by  simply  narrowing  at  one  point  the  calibre  of  the  tube  containing  the 
mercury,  either  by  a  stopcock,  or  by  reducing  the  tube  to  a  capillary  bore. 

Fallacies  of  Mercurial  Manometers.— The  oscillating  mercurial 
(.column  does  not  give  the  variations  in  blood-pressure  quite  truly,  because 
the  oscillations  are  compounded  of  these  variations  and  of  the  oscillations 
due  to  the  inertia  of  the  mercury  itself.  In  order  to  obtain  the  exact  form  of 
variation  we  employ  Fick's  kymograph  (Pig.  86),  or  Eoy's  tonometer,  in 
which  the  apparatus  is  made  very  light,  and  all  oscillations  due  to  its  own 
inertia  are  as  far  as  possible  avoided. 


Writing-point ' 


Piston  to  lessen  oscil- 
lation of  point. 

Tube      filled      with 
glycerine 


Eyringe  for    altering 
the  pressure  in  the 
I  manometer. 


—flat  metal  tube  form- 
ing the  manometer. 


(Tube  to  connect  the 
manometer  and  ar- 
tery. 


Fig.  86.— Pick's  kymograph.  It  consists  of  a  fiat  metal  tube,  bent  into  a  nearly  ciroular  form,  filled 
with  alcohol,  and  connected  with  the  artery  by  means  of  a  leaden  tube,  filled  with  a  solution  of 
sodium  carbonate.  When  the  pressure  increases  within  it,  the  tube  straightens,  and  when  the 
pressure  diminishes  it  bends.  These  changes  are  magnified  and  recorded  on  a  cylinder  by  a 
light  lever.  The  vibrations  of  the  lever  are  lessened  by  a  piston,  which  works  in  a  tube  rilled 
with  glycerine. 

Fallacies  from  Anaesthetics. — Even  if  the  instrument  be  free  from 
fallacy,  we  still  have  difficulty  in  ascertaining  the  real  action  of  the  drug  on 
the  circulation,  inasmuch  as  the  blood-pressure  is  much  affected  by  move- 
ments, and  by  anaesthetics.  If  the  animal  is  not  anaesthetised  we  may  get 
untrustworthy  results  from  the  straining  or  movements  it  may  make,  and  if 
it  is  anaesthetised,  the  anaesthetic  may  greatly  alter  the  power  of  the  heart,  or 
the  sensibility  of  the  nerve-centres  either  to  the  direct  action  of  the  drug 
upon  them,  or  to  its  reflex  action  through  the  afferent  nerves.  In  order  to 
get  rid  of  movement,  and  at  the  same  time  to  prevent  the  vascular  centres 
from  being  much  depressed,  curare  is  sometimes  used  instead  of  an  anaesthetic. 
Perhaps,  almost  equally  good  results  may  be  obtained  by  using  ether  as  the 
anaesthetic,  carefully  regulating  the  supply  so  as  to  abolish  sensation  without 
greatly  affecting  the  medulla.  The  reasons  why  this  is  possible  are  discussed 
at  p.  204.  In  order  to  regulate  the  supply  of  ether,  we  use  a  stopcock,  by 
which  pure  ether,  or  pure  air,  or  an  admixture  of  both  in  any  desired  propor- 
tion, can  be  passed  into  the  lungs  (Fig.  73,  p.  211). 

Other  fallacies  arise  from  the  mode  of  injecting  the  drug,  and  this  has 
Sometimes  led  to  false  results  :  thus  drugs  are  not  unfrequently  injected  into 
the  jugular  vein,  as  it  is  very  conveniently  situated  for  the  purpose.  In  this 
way,  however,  they  are  carried  directly  to  the  heart,  and  act  much  more 
strongly  upon  it,  than  they  would  do  if  absorbed  from  other  parts  of  the 
body.  In  the  case  of  irritant  salts,  for  example,  time  is  not  afforded  for  their 
irritant  properties  becoming  lessened  by  chemical  combination  with  the  con- 
stituents of  the  blood.     If  the  solution  injected  contain  particles  which  will 


270  PHAEMACOLOGY  AND  THEKAPEUTICS.      [sect,  i, 

not  pass  through  the  pulmonary  capillaries,  or  if  it  is  likely  to  cause  coagu- 
lation of  the  blood,  it  may  plug  up  the  pulmonary  vessels  and  give  rise  to 
dyspnoea  and  convulsions. 

Both  these  objections  are  avoided  when  the  drug  is  injected  under  the 
skin,  or  into  the  peritoneal  cavity.  Absorption  from  the  skin  is  slower  than 
from  the  peritoneum.  In  some  experiments  this  is  a  disadvantage :  in  others, 
however,  it  is  an  advantage. 

Another  fallacy  sometimes  arises  from  the  solution  of  carbonate  of  sodium 
used  to  prevent  coagulation.  In  order  to  prevent  the  blood  from  passing  too 
far  into  the  tube  connecting  the  artery  with  the  kymograph,  it  is  usual  to 
introduce  the  solution  of  carbonate  of  sodium  into  the  tube  by  a  syringe  (vide 
Fig.  86)  or  otherwise,  under  a  pressure  very  little  less  than  the  usual  blood- 
pressure  of  the  animal  experimented  on.  If  the  blood-pressure  be  lowered 
much  by  stoppage  of  the  heart  or  dilatation  of  the  vessels,  the  solution  of 
carbonate,  or  bicarbonate  of  sodium,  runs  into  the  arteries  and  may  cause 
convulsions  and  death.  Thus  stoppage  of  the  heart  by  irritation  of  the  vagus, 
or  by  the  action  of  a  drug,  may  sometimes  appear  to  be  followed  by  results  - 
which  are  not  really  due  to  it,  but  only  to  the  conditions  under  which  the 
experiment  has  been  made. 


Alterations  in  Blood-pressure. 

In  speaking  of  "blood-pressure,  arterial  blood-pressure  is  always 
meant,  unless  otherwise  stated. 

As  the  blood-pressure  depends  on  the  difference  between  the 
quantity  pumped  into  the  arterial  system  by  the  heart  at  one 
end,  and  the  quantity  flowing  out  through  the  arterioles  into  the 
veins  at  the  other  in  a  given  time,  it  is  evident  that — 

The  blood-pressure  will  remain  constant  when  these  quan- 
tities remain  equal  to  each  other. 

It  will  rise  when — 

(a)  More  blood  is  pumped  in  by  the  heart. 

(b)  When  less  flows  out  through  the  arterioles  in  a  given 

time. 
It  will  fall— 

(a)  When  less  is  pumped  in  by  the  heart ;  or, 

(b)  More  flows  out  through  the  arterioles ;  or,  to  look  at  it 

another  way : — - 

Heart  jmore  active-     Blood-pressure  rises. 
Uess        „  „  „       falls. 

Arterioles  {^tract  „  „       rises. 

ldllate  „  „       falls. 

The  heart  may  throw  more  blood  into  the  arteries,  either  by 
pulsating  more  rapidly,  or  by  pulsating  more  vigorously  and 
more  completely,  so  that  at  each  contraction  a  larger  amount  of 
blood  is  expelled.  But  increased  activity  can  only  affect  the 
blood-pressure  so  long  as  there  is  a  free  supply  of  blood  entering 
the  heart.  If  there  exist  any  obstruction  to  its  entrance  the 
increased  cardiac  action  will  have  no  effect.  Hence  obstruction 
of  the  pulmonary  circulation  will  also  lower  the  blood-pressure. 


-chap,  xi.]    ACTION  OF  DEUGS  ON  THE  CIECULATION.     271 

The  causes  of  alteration  in  the  blood-pressure  may  be  tabulated 
as  follows  :— 

Blood-Pressuve 


May  be  raised — 

1.  By  the  heart  beating 
more  quickly. 

2.  By  the  heart  beating 
more  vigorously  and  more 
completely,  and  sending  more 
blood  into  the  aorta  at  each 
beat. 

3.  By  contraction  of  the 
arterioles,  retaining  the  blood 
in  the  arterial  system. 


May  be  lowered — 

1.  By  the  heart  beating 
more  slowly. 

2.  By  the  heart  beating 
less  vigorously  and  completely, 
and  sending  less  blood  into  the 
aorta  at  each  beat. 

3.  By  dilatation  of  the 
arterioles,  allowing  the  blood 
to  flow  more  quickly  into  the 
Veins. 

4.  By  deficient  supply  of 
blood  to  the  left  ventricle,  as 
from  contraction  of  the  pul- 
monary vessels,  or  obstruction 
to  the  passage  of  blood  through 
them,  or  from  stagnation  of 
blood  in  the  large  veins,  e.g., 
in  shock. 

The  influences  on  the  pressure  exerted  by  (a)  the  number  of 
beats,  and  (b)  by  the  amount  of  blood  sent  out  by  the  heart  at 
each  beat,  to  a  certain  extent,  though  by  no  means  completely, 
counteract  each  other ;  for,  when  the  heart  is  beating  quickly, 
it  has  not  time  to  fill  completely,  and  so  sends  out  little  blood 
at  each  beat :  but,  when  beating  slowly,  it  becomes  quite  full 
during  each  diastole,  and  sends  out  a  larger  quantity  of  blood 
at  each  contraction. 

It  is  evident  that  the  amount  of  blood  which  the  heart  can 
send  into  the  arteries  at  each  beat  will  depend  also  upon  the 
completeness  with  which  the  ventricle  relaxes  during  diastole. 
If  the  relaxation  be  incomplete  very  little  blood  will  enter  the 
ventricle,  and  thus  a  drug  which  increases  the  contractile  power 
of  the  heart  may,  by  unnecessarily  prolonging  the  systole,  lower 
the  blood-pressure  as  much  as  a  drug  which  paralyses  the  heart 
and  prevents  the  ventricle  from  expelling  its  contents. 


Relation  of  Pulse-rate  and  Arterioles  to  Blood-pressure. 

Although  we  are  unable,  from  the  mere  fact  that  the  blood- 
pressure  rises  or  falls  after  the  administration  of  a  drug,  to  say 
whether  the  result  is  due  to  the  action  of  the  drug  on  the  heart 
or  on  the  arterioles,  yet  we  can  come  to  some  general  conclusion 
regarding  its  mode  of  action  by  comparing  the  alterations  which 


272  PHARMACOLOGY  AND  THERAPEUTICS,      [sect.  I. 

it  has  produced  in  the  blood-pressure  with  those  which  occur  m 
the  pulse-rate.  For  in  the  normal  condition  of  an  animal*  when 
all  the  nerves  are  intact,  a  rise  in  the  blood-pressure  renders  the 
pulse  slow  by  increasing  the  normal  tone  of  the  vagus  centre  in 
tbe  medulla,  and  a  fall  of  blood-pressure  quietens  the  pulse  by 
diminishing  the  tone.  This  mechanism  tends  in  the  normal 
animal  to  keep  the  blood-pressure  more  or  less  constant. 

We  find,  therefore,  that  when  alterations  in  blood-pressure 
and  pulse-rate  are  depicted  graphically,  so  that  a  rise  in  one 
curve  indicates  a  rise  in  blood-pressure,  and  a  rise  in  the  other 


Fig.  87.— Diagram  of  a  pulse  and  blond-pressure  curve,  where  tbe  alterations  are  due  at  first  to  the 
action  of  a  drug  on  the  heart,  as  in  tbe  case  of  atropine.  The  unbroken  line  indicates  tbe  blood- 
pressure,  and  the  dotted  line  the  pulse.  After  the  injection  shown  by  the  vertical  line  the  vagus 
is  paralysed,  the  pulse  becomes  very  rapid,  and  the  blood-pressure  rises.  At  A  the  vaso-motor 
centre  becomes  paralysed,  the  arterioles  dilate,  and  the  pressure  falls.  From  a  to  6  the  action 
of  the  heart  continues  nearly  uniform,  notwithstanding  the  fall  in  blood-pressure,  but  at  6  the 
heart  begins  to  become  paralysed,  and  the  pulse-rate  and  blood-pressure  both  continue  to  fall 
steadily  till  death. 

indicates  quickening  of  the  pulse,  the  two  curves  run  in  oppo- 
site directions  if  the  alteration  in  blood-pressure  is  due  to  the 
arterioles,  but  they  run  parallel  when  the  alteration  is  due  to 
the  heart  (Fig.  87).  Thus,  if  the  vagi  be  cut,  we  find  that  the 
pulse-rate  rises,  and  in  consequence  of  this  the  blood-pressure  also 
rises.  Here  the  alteration  in  pressure  is  due  to  the  heart,  and 
the  two  curves  are  therefore  parallel.  If  the  vagi  be  irritated  the 
pulse-rate  falls,  and  in  consequence  of  this  the  blood-pressure  also 
falls.  Here  again  the  alteration  is  due  to  the  heart,  and  the  two 
curves  are  parallel. 


Fig.  88.— Diagram  of  pulse  and  blood-pressure  curves,  where  the  alterations  are  lue  at  first  to  the 
action  of  a  drug  on  the  arterioles.  The  unbroken  line  indicates  the  blood-pressure,  the  dotted 
line  indicates  the  pulse.  The  upright  line  indicates  the  time  of  iujectiun  of  the  poison.  This 
is  followed  by  contraction  of  the  arterioles  and  consequent  rise  of  blood-pressure.  This  rise 
stimulates  the  vagus  roots,  and  causes  slowness  of  the  pulse.  At  6  the  vagus  becomes  paralysed, 
the  pulse  becomes  quick,  and  the  pressure  rises  still  higher  between  A  and  B.  At  B  the  vaso- 
motor centre  becomes  paralysed,  the  arterioles  dilate,  and  the  pressure  falls,  notwithstanding 
the  rapidity  of  the  pulse.  At  c  the  heart  itself  begins  to  be  paralysed,  its  beats  become  slow, 
and  both  pulse  and  pressure  fall  steadily  till  death. 

If,  on  the  other  hand,  the  arterioles  are  made  to  contract  the 
pressure  rises,  but  the  increased  pressure  stimulates  the  vagus 
roots  in  the  medulla  and  the  pulse-rate  falls,  so  that  the  curves 


chap,  xi.]    ACTION  OF  DEUGS  ON  THE  CIECULATION.     273 

run  in  opposite  directions.  If  the  arterioles  dilate  the  pressure 
falls,  and  the  vagus  tone  being  lessened  the  pulse-rate  rises ;  so 
the  curves  are  again  in  opposite  directions  (Fig.  88). 

An  example  of  this  is  seen  in  the  accompanying  curve  (Fig.  89), 
which  illustrates  the  action  of  erythrophloeum — a  substance  similar 
in  action  to  digitalis— on  the  circulation.  After  the  injection  of 
the  drug  the  vessels  contract,  and  the  blood-pressure  consequently 
rises  and  produces  some  slowness  of  the  pulse.  In  a  little  while 
the  vagus  becomes  paralysed,  the  pulse  becomes  quicker,  and 


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Jia.  89.— Curve  of  the  pulse  and  blood-pressure  in  a  cat  after  division  uf  the  spinal  cord  at  the  atlas 
and  injection  of  erythrophloeum.    (Prom  a  paper  by  Brunton  and  Pye,  Phil.  Trans,  vol.  167.) 

the  pressure  rises  still  further.  At  a  later  stage  the  heart  be- 
comes slow,  apparently  from  the  action  of  the  drug  upon  it,  and 
the  blood-pressure  then  falls  again.  At  first  then,  where  the 
alteration  of  pressure  depends  upon  the  state  of  the  vessels,  we 
have  the  two  curves  running  in  opposite  directions,  but  when 
the  alterations  depend  upon  the  condition  of  the  heart  we  have 
them  running  parallel.1  It  will  be  noticed  that  in  the  latter  part 
of  the  curve,  although  the  blood-pressure  and  the  pulse  sink 

1  Although  the  rise  in  blood-pressure  which  accompanies  that  of  the  pulse  ia 
partly  due  to  the  heart,  it  is  very  probable  that  the  contraction  of  the  arterioles 
which  caused  the  rise  at  first  is  not  only  continuing  but  increasing. 


274     .       PHARMACOLOGY  AND  THEEAPEUTICS.     [sect.  I. 

together,  they  do  hot  sink  quite  parallel ;  the  pulse  falling  very 
rapidly  and  the  blood-pressure  very  slowly.  Prom  this  fact  we 
may  conclude  that  the  arterioles  are  still  contracted,  and  this 
affords  an  illustration  of  another  way  in  which  we  judge  of  the 
effect  of  drugs  upon  the  arterioles.  This  conclusion  would  not 
be  warranted  by  the  data  contained  in  Fig.  89  alone.  For  the 
slowness  with  which  the  blood-pressure  falls  in  this  experiment 
might  possibly  be  due  to  the  heart  beating  more  perfectly,  at  the 
same  time  that  it  begins  to  beat  more  slowly.  An  examination 
of  the  original  tracings  of  the  blood-pressure  shows  that  this  is 
not  the  case  and  that  the  beats  of  the  heart  became  feeble  at  the 
same  time  that  they  became  slow. 

The  mutual  regulating  power  of  the  pulse  and  blood-pressure 
only  exists  when  the  vagi  are  working  normally.  If  they  should 
be  paralysed,  either  by  section  or  by  the  action  of  a  drug,  in- 
creased arterial  pressure  will  no  longer  slow  the  pulse ;  it  may 
even  quicken  it,  and  therefore  the  pulse-rate  and  blood-pressure 
may,  in  such  a  condition,  run  parallel  even  though  the  increased 
pressure  should  be  dependent  upon  alterations  in  the  arterioles. 

But  if  the  vagi  are  not  paralysed,  and  we  find  on  comparing 
the  curves  of  blood-pressure  and  pulse-rate  that  they  run  parallel, 
a  fall  in  the  blood-pressure  and  slowness  of  pulse  occurring 
together,  or  a  rise  in  pressure  and  quickness  of  pulse  accom- 
panying each  other,  we  may  conclude  that  the  alterations  in 
such  a  case  are  due  to  changes  in  the  action  of  the  heart. 

If,  however,  we  find  that  the  curves  run  in  opposite  directions, 
the  pressure  rising  and  the  pulse  falling,  it  is  highly  probable 
that  the  rise  is  due  to  contraction  of  the  arterioles,  and  that  the 
fall  of  the  pulse  is  caused  by  the  rise  of  pressure  acting  as  a 
stimulus  to  the  vagus  roots.  This  is,  however,  not  quite  certain, 
as  it  might  be  due  to  the  action  of  the  drug  upon  the  vagus,  and 
the  proper  method  of  ascertaining  this  would  be  that  employed 
by  Ludwig,  of  allowing  a  quantity  of  blood  to  flow  out  into  a 
bladder  connected  with  a  blood-vessel,  so  that  the  pressure, 
should  fall.  If  the  pulse  still  continued  slow  in  spite  of  the  fall 
of  pressure,  it  would  be  evident  that  the  slowness  was  due  to  the 
action  of  the  drug  upon  the  vagus,  and  not  to  indirect  action 
through  the  blood-pressure.  By  employing  a  bladder  in  this 
manner  the  blood  can  be  quickly  introduced  again  into  the 
vessels  after  the  effect  of  its  withdrawal  has  been  ascertained. 

We  not  unfrequently  find  that,  owing  to  the  action  of  a  drug 
the  pulse,  which  has  become  slow  during  the  rise  of  the  blood- 
pressure,  suddenly  becomes  very  rapid  notwithstanding  that  the 
pressure  continues  high.  This  is  usually  due  to  paralysis  of  the 
vagus-ends  in  the  heart,  and,  when  this  occurs,  the  correctness 
of  the  conclusion  which  we  draw  from  the  occurrence  mav  be 
ascertained  by  stimulating  the  vagus  in  the  neck  by  a  faradaic 
current,  and  seeing  whether  any  slowing  or  stoppage  of  the  heart 


chap,  xi.]    ACTION  OF  DEUGS  ON  THE  CIRCULATION.     275  _• 

occurs.  Frequently  we  find  that  after  the  pulse  has  become 
quick  from  paralysis  of  the  vagus,  the  pressure  which  the  quick- 
pulse  had  raised  begins  to  fall  again  from  paralysis  of  the 
arterioles.  The  pulse  may  continue  quick  and  weak  almost  till 
death  and  then  cease  suddenly,  or  it  may  become  gradually  slow 
as  well  as  weak  from  paralysis  of  the  heart  itself. 

Effect  of  the  Arterioles  on  Pulse-curves. — The  influence  of 
the  arterioles  upon  the  blood-pressure  in  a  living  animal  can  be 
to  a  great  extent  ascertained  by  the  rapidity  or  slowness  of  the , 
fall  of  the  blood  pressure  during  the  diastole  of  the  heart.  When 
the  heart  is  beating  slowly  the  diastole  may  be  long  enough  to 
show  distinctly  the  curve  which  the  blood-pressure  describes  dur- 
ing its  descent ;  but  if  the  heart  is  beating  quickly  the  diastole 
may  be  so  short  that  this  curve  cannot  be  exactly  obtained.  It  is 
then  necessary  to  prolong  the  diastole  artificially  by  stimulation 
of  the  vagi. 

The  reason  why  the  part  which  the  arterioles  play  in  main- 
taining the  blood-pressure  can  be  ascertained  by  the  way  in 
which  it  falls  during  cardiac  diastole,  natural  or  artificial,  is  that 
in  the  healthy  heart  the  aortic  valves  close  during  the  diastole  so 
as  to  separate  the  aorta  completely  from  the  ventricle. 

In  considering  the  blood-pressure  during  the  diastole,  we  may 
therefore  disregard  the  heart  entirely,  and  look  upon  the  aorta 
and  its  branches  as  an  elongated  elastic  bag  closed  at  its  cardiac 
end,  but  open  at  its  capillary  end.  This  bag  is  distended  with 
blood,  which  in  consequence  of  the  elastic  pressure  exerted  upon 
it  by  the  arterial  walls  tends  to  flow  out  into  the  veins.  The 
rate  at  which  it  does  this  will  depend — 

1st,  on  the  elastic  pressure  or  arterial  tension ;  and, 

2ndly,  on  the  size  or  degree  of  contraction  of  the  arterioles  or 
capillaries. 

If  we  connect  a  manometer  with  this  elongated  bag  as  in 
Fig.  90,  and  place  on  the  mercurial  column  a  float  by  which  its 


Fig.  90.— Diagram  of  the  circulation,  a,  the  heart,  completely  shut  off  by  the  valves  during 
diastole  from  b,  the  arteries,  e,  the  capillaries,  d,  the  veins,  e,  mercurial  manometer.  /,  a 
float,    g,  a  recording  cylinder. 

height  can  be  recorded  on  a  revolving  cylinder,  it  is  evident  that 
the  pressure-curve  will  fall  more  quickly  to  zero  when  the  capil- 
laries are  dilated,  and  more  slowly  when  they  are  contracted. 
With  capillaries  of  the  same  size,  the  rate  of  flow  will  vary 

T  2 


276  PHAKMACOLOGY  AND  THERAPEUTICS,      [sect.  i. 

with  the  arterial  pressure.  If  the  pressure  be  high  the  curve 
will  fall  more  rapidly  than  when  it  is  low,  for  the  greater  blood- 
pressure  will  drive  the  blood  more  rapidly  through  the  open 
arterioles.  If  we  find  that  with  a  normal  pressure  the  pressure- 
curve  falls  more  slowly  than  usual  during  the  diastole,  we  may 
conclude  that  the  arterioles  are  contracted ;  and  if  we  find  that 
the  fall  is  slower,  notwithstanding  that  the  pressure  is  higher 
than  usual,  the  proof  that  the  arterioles  are  contracted  is  so 
much  the  stronger. 

This  is  what  Meyer  and  I  *  observed  in  the  case  of  digitalis, 
where  we  found,  as  in  the  accompanying  figure  (Fig.  91),  that 
the  fall  of  the  blood-pressure  during  the  cardiac  diastole  hi  a 
dog  is  much  slower  after  than  before  the  injection  of  digitalis 
into  the  circulation. 

In  observations  of  this  sort  it  must  always  be  borne  in  mind 
that  a  great  difference  exists  between  the  vessels  of  the  intestines 


2?ig.  91.— Tracing  showing  tlie  blood-pressure  and  form  of  the  pulse-wave  before  and  after  the  in- 
fection of  digitalis  -in  the  dog.  The  thin  line  shows  the  blood-pressure  before,  and  the  thick 
one  after,  the  injection.  The  curve  sinks  more  slowly  after  the  injection,  notwithstanding  the 
greater  pressure  in  the  vessels. 

on  the  one  hand,  and  those  of  the  muscles  on  the  other.  The 
former  are  readily  controlled  by  the  vaso-motor  centre,  and 
when  this  is  stimulated  they  contract  greatly.  Those  of  the 
muscles  appear  to  be  but  slightly  influenced  by  the  vaso-motor 
centre,  so  that  when  it  is  stimulated  they  hardly  contract  at  all, 
and  indeed  the  flow  of  blood  through  them  becomes  accelerated 
on  account  of  the  contraction  of  the  vessels  elsewhere.  When 
the  vaso-motor  centre  is  stimulated  at  the  same  time  that  the 
vagus  is  irritated,  the  blood-pressure  appears  to  fall  nearly  as 
quickly  as  when  the  vagus  alone  is  irritated.  It  seems  possible, 
however,  that  this  result  may  be  really  due  to  some  extent  to 
actual  dilatation  of  the  vessels  in  the  muscles,  for  stimulation  of 
the  motor  nerves  of  muscle  appears  to  produce  a  vaso-dilating 
effect  on  their  blood-vessels  (Gaskell  and  others) . 

The  want  of  power  of  the  vaso-motor  centre  over  the  vessels 

1  Brunton  and  Meyer,  Journal  of  Anatomy  and  Physiology,  vol.  vii.  1872,  p.  134. 
The  experiments  described  in  the  paper  were  performed  in  1868. 


chap,  si.]    ACTION  OF  DEUGS  ON  THE  CIECULATION.     277 

of  the  muscles  is  probably  of  considerable  pathological  import- 
ance. John  Hunter  *  noticed,  when  he  was  bleeding  a  lady  from 
a  vein  in  the  arm,  that  the  blood,  which  previously  had  been 
dark  and  venous,  became  bright  scarlet,  like  arterial  Wood,  when 
she  fainted,  and  remained  so  during  the  continuance  of  the  faint. 
This  seems  to  indicate  that  during  syncope,  although  the  super- 
ficial vessels  are  empty  and  contracted,  the  arterioles  of  the 
muscles  are  dilated  like  those  of  an  actively  secreting  salivary 
gland. 

If  we  find,  then,  that  after  the  injection  of  a  drug  the  blood- 
pressure  remains  constantly  high,  during  stoppage  of  the  heart, 
we  may  conclude  that  the  vessels  of  the  muscles  are  contracted 
as  well  as  those  of  the  intestine.  Such  a  condition  occurs  after 
the  injection  both  of  digitalin  and  of  erythrophlceum,  in  which 
the  pressure  sometimes  remains  high  for  many  seconds,  or  even 
for  a  minute  or  more,  after  the  heart  has  finally  ceased  to  beat 
(Fig-  89). 

Investigation  of  the  Action  of  Drugs  on  the  Arterioles. 

The  arterioles  become  contracted  by  the  action  of  the  involun- 
tary muscular  fibre  contained  in  their  walls ;  they  dilate  partly 
by  their  own  elasticity  and  partly  by  the  pressure  of  fluid  within 
them; 

The  capillaries  also  appear  to  have  the  power  of  contraction. 
Both  arterioles  and  capillaries  are  induced  to  contract  by  the 
effect  upon  them  of  the  nerves  which  pass  to  them  from  vaso- 
motor centres.  The  blood-vessels  may  also  dilate  actively  from 
irritation  of  vaso-inhibitory  nerves.  The  exact  mode  of  action 
of  these  nerves  is  not  ascertained;  they  are  generally  looked 
upon  as  entirely  separate  from  vaso-motor,  but  it  seems  not  im- 
probable that  here  also  the  difference  between  vaso-motor  and 
vaso-inhibitory  nerves  is  a  mere  question  of  relation,  and  some 
nerves  produce  contraction  and  dilatation  according  to  the  point 
where  they  are  stimulated.  Thus  Dastre  and  Morat  have  found 
that  the  cervical  sympathetic,  which  produces  contraction  of  the 
vessels  in  the  rabbit's  ear  when  irritated  between  the  ear  and  the 
first  thoracic  ganglion,  causes  dilatation  instead  of  constriction 
when  it  is  irritated  at  a  point  below  the  ganglion,  in  which  case 
the  stimulus  has  to  pass  through  the  ganglion  before  it  reaches 
the  ear. 

In  considering  the  action  of  drugs  on  the  vessels,  we  have, 
therefore,  to  examine — 

1.  Their  direct  effect  upon — 

a.  The  contractile  walls  of  the  vessels  themselves  with  their 
a,  muscular  fibres, 
o,  motor  ganglia ; 

1  John  Hunter's  works,  edited  by  Palmer,  1837,  vol.  iii.  p.  91, 


273  PHAEMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

B.  Nerve-fibres 

a,  vaso-motor, 

b,  vasodilating ; 
c.  Nerve-centres 

a,  vaso-motor, 

b,  vaso-dilating. 

2.  Their  reflex  effect  on  the  nerve-centres  just  mentioned. 

There  are  two  modes  of  estimating  the  contraction  of  the 
arterioles  :  1st,  by  direct  observation  and  measurement  under  the 
microscope ;  2nd,  by  ascertaining  the  quantity  of  blood  or  other 
fluid  which  will  pass  through  them  in  a  given  time. 

Each  of  these  methods  may  be  used  in  several  ways,  accord- 
ing as  we  wish  to  ascertain  the  action  of  a  drug— 1st,  on  the 
contractile  walls  of  the  vessels  alone  ;  2nd,  on  the  walls  together 
with  the  vascular  nerves  but  without  the  nerve-centres ;  and  3rd, 
on  the  vessels  in  connection  with  the  nerve-centres. 

The  method  of  direct  observation  of  the  arterioles  may 
be  practised  in  either  frogs  or  mammals. 

The  part  of  the  frog  usually  selected  is  the  web,  the  mesen- 
tery, the  mylo-hyoid  muscle,  the  tongue,  or  the  lung.  The  parts 
usually  observed  in  mammals  are  the  wing  of  the  bat  and  the 
ear  of  the  rabbit.1 

In  observing  the  effect  of  various  conditions  on  the  lung,  it 
is  necessary  to  inflate  it.  This  is  easily  done  by  means  of  a 
small  cannula  with  a  bulging  end  which  is  tied  into  the  larynx. 
Over  the  other  end  is  slipped  a  small  piece  of  india-rubber 
tubing,  and  by  clamping  this  after  the  lung  has  been  inflated, 
the  escape  of  air  is  prevented. 

An  apparatus  for  this  purpose  is  described  by  Holmgren.2 
The  accompanying  engraving  (Fig.  92)  shows  one  which  I  used 
in  1870  for  the  purpose  of  investigating  the  action  of  heat  and 
cold  upon  the  lung.3 

By  means  of  the  india-rubber  ball  I  directed  upon  the  lung 
a  stream  of  air  which  was  previously  passed  either  through  hot 
water  or  through  iced  water.  The  pulmonary  capillaries,  when 
treated  in  this  way,  contract  under  the  influence  of  cold  by  one- 
third  of  their  diameter.  McKendrick,  Coats,  and  Newman,  in 
an  investigation  on  the  action  of  anaesthetics  on  the  pulmonary 
circulation,  found  that  chloroform,  ethidene,  and  ether,  all  stop 
the  pulmonary  circulation,  the  action  of  chloroform  being  greatest 
■and  that  of  ether  least.4 

In  observing  the  effects  of  drugs  on  the  vessels  alone,  it  is 
necessary  to  destroy  the  influence  of  the  nerve-centres  over  them. 

1  For  observing  the  vessels  of  the  rabbit's  ear  one  of  Bracke's  lenses  is  very- 
convenient.    It  resembles  a  telescope  in  its  construction,  but  has  a  very  short  focus. 

2  Ludwig's  Festgabe. 

s  British  Medical  Journal,  Feb.  13,  1875,  p.  204. 
4  Ibid.  Dee.  18,  1880. 


chap,  xi.]    ACTION  OF  DKUGS  ON  THE  CIRCULATION.    279 

This  is  usually  done  in  a  frog  by  destroying  the  brain  and  spinal 
cord.  In  the  rabbit's  ear  it  is  done  by  dividing  as  far  as  possible 
all  the  nerves  going  to  one  ear,  then  injecting  the  drug  into  the 
general  circulation  and  comparing  its  effect  upon  the  two  ears. 


Piu,  y2. — Apparatus  for  ascertaining  the  effect  of  heat  and  cold  on  the  vessels  of  the  frog's  lungs. 
A,  a  piece  of  cork  to  which  the  frog  is  fastened,  is  iaid  on  b,  the  stage  of  a  microscope,  and 
attached  by  an  india-rubber  strap,  c.  D  is  a  small  ring  of  cork  covered  witha  thin  circle  of  glass. 
e  is  the  inflated  frog's  lung,  p  is  a  tube  by  which  a  current  of  air  can  be  directed  on  the  frog's 
lung.  It  is  held  in  position  by  a  piece  of  wire,  o,  which  can  be  bent  to  any  position,  z  isanask 
containing  ice  and  water.  H,  a  flask  containing  hot  water.  K  is  a  three-way  stopcock,  by  which 
a  current  of  air  may  be  sent  from  the  spray-producer,  L  and  M,  through  either  I  or  H  at  will,  and 
thus  cold  or  hot  air  may  be  applied  alternately  to  the  lung. 

It  is  evident,  however,  that  such  experiments  are  not  free  from 
fallacy,  because  in  them  the  circulation  is  dependent  on  the 
condition  of  the  heart  as  well  as  that  of  the  vessels ;  and  both  of 
these  may  be  affected  by  the  drug. 

A  better  plan,  therefore,  is  to  obviate  this  fallacy  by  keeping 


280  PHAKMACOLOGY  AND  THEKAPEUTICS.      [sect,  i. 

up  the  circulation  artificially,  either  in  the  body  of  the"  frog,  of 
in  the  ear  of  the  rabbit. 

A  method  of  maintaining  artificial  circulation  in  the  rabbit's 
ear  while  the  calibre  of  the  vessels  is  being  measured  was  in- 
vented by  Ludwig,  and  described  by  me  in  the, British  Medical 
Journal,  1871. 

In  the  frog  artificial  circulation  is  kept  up  by  putting  a 
cannula  into  the  aorta,  and  another  into  the  vena  cava  or  abdo- 
minal vein  after  destruction  of  the  brain  and  spinal  cord.  The 
aortic  cannula  is  connected  with  two  funnels  or  bottles,  such  as 
are  used  for  artificial  circulation  through  the  intestine  (p.  382). 
These  contain  either  a  saline  solution  or  a  mixture  of  saline  solu- 
tion with  defibrinated  blood.  To  one  of  them  the  drug  is  added. 
The  circulation  can  be  rendered  quicker  or  slower  at  will,  by  in- 
creasing the  pressure  under  which  the  fluid  flows  into  the  aorta. 
A  suitable  part  of  the  frog  is  then  put  under  the  microscope,  and 
the  vessels  measured  wbile  unpoisoned  blood  flows  through  them. 
The  poisoned  blood  is  then  allowed  to  circulate  under  exactly  the 
same  conditions  of  pressure  and  the  vessels  are  measured  again. 
By  this  method  of  observation  (iraskell  ascertained  that  very 
dilute  alkalies  cause  great  contraction  of  the  vessels,  so  as  some- 
times almost  entirely  to  occlude  them  and  arrest  any  flow  of 
blood  through  them.  Dilute  acids  counteract  this  effect  and 
cause  the  vessels  again  to  dilate. 

Cash  and  I  have  observed  that,  in  addition  to  this  action, 
dilute  acids  have  a  tendency  to  increase  the  exudation  of  fluid 
from  the  vessels  and  produce  oedema  of  surrounding  tissues. 

In  many  experiments  which  have  been  made  on  the  action  of 
drugs  on  the  blood-vessels  by  direct  microscopic  measurement  of 
their  size,  before  and  after  the  application  of  the  drug,  no  ac- 
count has  been  taken  of  the  effect  which  the  application  of  the 
drug  may  produce  by  its  local  irritating  action  on  the  nerves  or 
tissues  of  the  part  to  which  it  is  applied,  and  by  its  reflex  action 
through  the  nerves,  quite  independently  of  any  special  action 
which  it  may  have  on  the  vessels.  Thus,  irritation  by  the  appli- 
cation of  alcohol,  either  alone  or  as  a  solvent  in  tinctures,  or  by 
a  strong  saline  solution,  has  an  effect  similar  to  that  of  simple 
irritation  by  pressure  or  scratching,  and  usually  causes  tempo- 
rary contraction,  followed  by  dilatation  of  the  capillaries.  This 
contraction  may  be  more  or  less  prolonged,  according  to  the 
strength  of  the  irritant  which  is  applied.  Unless  these  condi- 
tions are  taken  into  account,  observations  on  the  effect  of  drugs 
applied  locally  to  the  web,  mesentery,  or  tongue,  are  very  un- 
satisfactory and  generally  worthless. 

Perhaps  a  somewhat  better  result  may  be  obtained  by  in- 
jecting the  drug  into  the  lymph-sac  of  a  frog,  and  then  observing 
the  web.  But  here  also  we  have  the  same  difficulty,  because  the 
sensory  nerves  of  the  lymph-sac  being  irritated,  reflex  stimulation 


chap,  xi.]    ACTION  OF  DRUGS  ON  THE  CIRCULATION.     281 


of  the  vaso-motor  centre  and  consequent  contraction  of  the  vessels 
may  be  induced. 

Method  of  Measurement  by  Rate  of  Flow.— Another 
method  of  ascertaining  the  effect  of  drugs  on  the  vessels  is  to 
measure  the  amount  which  flows  out  of  them  in  a  given  time. 
This  method  may  be  employed  either  in  the  frog  or  in  the  higher 
animals.  The  method  of  employing  it  in  the  frog  is  to  destroy 
the  brain  and  spinal  cord,  and  tie  one  cannula  into  the  heart  or 
aortic  bulb,  and  another  into  the  inferior  vena  cava.  The  aortic 
cannula  is  connected  with  a  reservoir  containing  saline  solution,  or 
defibrinated  blood,  which  can  be  made  to  pass  into  the  aorta  and 
circulate  through  the  vessels  at  any  desired  pressure  by  simply 
raising  or  lowering,  the  reservoir ;  the  fluid  flows  out  through  the 
cannula  in  the  vena  cava,  and  the  quantity  is  registered  upon  a 
revolving  cylinder. 

By  this  method  Cash  and  I  have  found  that  potassium 
chloride,  contrary  to  our  expectation,  causes  great  contraction 
of  the  vessels ;  that  barium  and  calcium  and  strontium  do  so 
also,  but  to  a  less  extent.  The  instrument  used  for  this  purpose 
consists  of  a  light  lever,  one  end  of  which  is  depressed  each  time 
that  a  drop  falls  upon  it.  An  electric  circuit  is  thus  broken,  and 
the  fall  of  each  drop  is  readily  recorded  by  means  of  an  electro- 
magnetic marker ;  at  the  same  time  the  pressure  under  which  the 
circulation  is  going  on  is  also  recorded  by  means  of  a  manometer. 
Slowing  of  the  flow  indicates  of  course  contraction  of  the  vessels, 
and  acceleration  indicates  dilatation  of  the  vessels. 

The  general  results  of  our  experiments  with  several  metallic 
salts  are  shown  in  the  accompanying  table.  Most  of  the  drugs 
experimented  on  cause  contraction  of  the  blood-vessels,  but  we 
are  unable  at  present  to  arrange  them  in  the  exact  order  of  their 
strength  of  action. 

Lithium  causes  slight  contraction.  Iron    causes  slow  contraction. 

Potassium  (very  dilute  solutions)  causes 
dilatation. 
Ditto  (solutions  of  j^g)  causes  con- 
traction. 

Barium    causes  rapid  contraction. 

Calcium        „    gradual        „ 

Strontium     „    gradual        „ 

Magnesium  „    slight  „ 

Aluminium  (much  diluted)  has  no  effect. 
1  per  cent,  needed  to  produce  any 
effect. 

In  experiments  made  by  such  methods  as  that  just  described 
we  reduce  the  problem  of  the  action  of  drugs  on  the  blood-vessels 
to  a  very  simple  form,  although  we  have  still  to  distinguish 
whether  the  drug  acts  directly  on  the  contra1  ctile  walls  of  the 
blood-vessel  or  on  the  nervous  elements  contained  in  them. 
There  is  at  present  no  means  of  absolutely  separating  those  two 
factors,  but  it  is  probable  that  the  nerves  die  sooner  than  the 


Copper 

,    powerful  , 

Zinc         , 

»           11         * 

Tin 

i          »»         » 

Cadmium 

,     slight       , 

Nickel 

i        j»           i* 

Cobalt 

ti        "           i) 

Platinum 

,    powerful  , 

but  none 
is  produced  by  solutions  weaker  than 

i 
Eooo* 


282  PHARMACOLOGY  AND  THEEAPEUTICS.      [sect.  i. 

muscular  fibres,  and  that  if  the  experiments  are  carried  on  for 
some  time  the  effect  of  the  drug  is  chiefly,  if  not  entirely,  exerted 
upon  the  muscular  fibres.  This  is  probably  the  explanation  of 
the  different  effects  of  chloral  on  the  vessels  of  the  kidney  observed 
by  Ludwig  and  Mosso  (p.  283). 

In  experiments  on  the  flow  of  blood  through  the  vessels  of 
warm-blooded  animals,  the  circulation  is  kept  up  in  much  the 
same  way  as  in  the  frog.  The  blood  may  be  used  cold,  or  may 
be  kept  at  the  temperature  of  the  body.  The  cannula  is  usually 
inserted  either  into  the  artery  supplying  an  organ  such  as  the 
kidney,  or  supplying  a  single  muscle,  or  it  may  be  put  into  the 
descending  aorta,  so  that  the  blood  passes  through  the  whole  of 
both  lower  extremities.  The  flow  is  measured  by  the  rate  at 
which  the  blood  issues  from  the  corresponding  vein. 

This  method  we  owe  to  Ludwig,  who,  along  with  his  pupil 
Mosso,  made  a  number  of  experiments  on  the  circulation  through 
the  kidney.  The  conclusions  arrived  at  were : — that  venous  blood 
causes  contraction,  and  oxygenated  blood,  dilatation  of  the  ves- 
sels; but  the  dilatation  which  richly  oxygenated  blood,  circulating 
after  venous  blood,  causes  in  the  vessels  is  only  temporary,  and 
they  soon  return  to  their  normal  calibre.  Mosso's  experiments 
have  been  repeated  by  Severini,  who  used  the  lung  instead  of  the 
kidneys.  He  finds  that  the  alternate  circulation  of  oxygenated 
and  of  venous  blood  acts  in  the  manner  described  by  Mosso, 
but  that  when  oxygenated  blood  is  passed  through  steadily  the 
vessels  contract  and  the  flow  through  them  is  diminished ;  venous 
blood,  on  the  contrary,  when  circulated  for  a  length  of  time  causes 
the  vessels  to  dilate  and  the  flow  through  them  to  increase.  The 
action  of  venous  blood  upon  the  arterioles  appears  indeed  to  be 
similar  to  its  action  upon  other  tissues.  A  small  or  moderate 
quantity  of  carbonic  acid  acts  as  a  stimulus  and  causes  contrac- 
tion, but  great  interference  with  the  natural  process  of  oxidation 
produces  paralysis. 

Nicotine,  in  the  proportion  of  1  in  10,000,  causes  contraction 
of  tbe  vessels ;  but  this  is  also  temporary.  One  per  cent.,  on 
the  contrary,  immediately  causes  dilatation. 

Atropine  has  a  very  powerful  action ;  but  this  differs  com- 
pletely according  to  the  dose.  One  part  in  100,000  causes  tem- 
porary contraction  of  the  vessels,  which  soon  passes  off.  One 
in  10,000  causes  contraction,  which,  instead  of  returning  simply 
to  the  normal,  passes  into  dilatation,  and  then  returns  to  the 
normal.  One  in  5,000  has  a  similar  action,  but  instead  of  the 
dilatation  passing  away,  and  the  vessels  returning  to  their  normal 
size,  the  dilatation  persists,  and  the  kidney  soon  dies. 

Chloral  causes  the  vessels  to  contract  and  then  to  dilate ;  but 
besides  this  it  has  a  peculiar  action,  either  increasing  rhythmical 
contraction  and  dilatation  of  the  vessels,  when  such  movements 
are  already  present,  or  inducing  them  when  they  are  absent.    It 


chap,  xi.]    ACTION  OF  DRUGS  ON  THE  CIRCULATION.     283 

only  acts  upon  the  vessels  when  the  blood  contains  oxygen ;  and 
when  the  blood  is  saturated  with  carbonic  acid,  it  has  no  action 
on  them  at  all.  Its  action  is  also  altered  by  the  condition  of  tbe 
kidney.  When  this  organ  has  been  kept  for  twenty-four  hours 
in  a  cool  place,  its  vessels  still  retain  their  irritability  ;  but  small 
doses  of  chloral,  instead  of  causing  contraction  followed  by  dila- 
tation, only  produce  contraction,  and  a  much  larger  dose  is 
required  to  produce  dilatation.  This  alteration  is  due  to  a 
change  in  the  vessels— either  in  their  muscular  walls,  or  more 
probably  in  the  ends  of  the  vaso-motor  nerves — and  not  to  any 
change  in  the  blood ;  for  it  occurs  when  serum  instead  of  blood 
is  passed  through  the  kidneys.  When  the  kidney  is  dead,  chloral 
mixed  with  the  blood,  instead  of  increasing  the  rapidity  of  the 
current  as  in  the  living  organ,  or  leaving  it  unaltered,  as  one 
would  expect,  greatly  diminishes  it.  Chloral  also  alters  the  effect 
of  artificial  stimulation  of  the  kidney.  Faradaic  currents  or  in- 
duction-shocks do  not  seem  to  affect  the  normal  vessels,  but 
constant  currents  cause  dilatation,  which  continues  while  the 
currents  are  passing  and  diminishes  after  they  cease.  When 
chloral  is  added  to  the  circulating  blood,  however,  the  vessels 
contract  during